Substituted pyrazolo[4,3-b]pyridines and their use as GluN2B receptor modulators

ABSTRACT

Substituted pyrazolo[4,3-b]pyridines as GluN2B receptor ligands. Such compounds may be used in GluN2B receptor modulation and in pharmaceutical compositions and methods for the treatment of disease states, disorders, and conditions mediated by GluN2B receptor activity.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the priority benefit of U.S. provisionalapplication No. 62/861,674, filed Jun. 14, 2019, the contents of whichare incorporated herein in their entireties by reference thereto.

FIELD OF THE INVENTION

The present invention is related to compounds having GluN2B modulatingproperties, pharmaceutical compositions comprising these compounds,chemical processes for preparing these compounds and their use in thetreatment of diseases associated with GluN2B receptor activity inanimals, in particular humans.

BACKGROUND OF THE INVENTION

Glutamate is one of the major excitatory neurotransmitters that iswidely spread in the brain.

First indication of its role as an excitatory messenger was in the1950's when it was observed that intravenous administration of glutamateinduces convulsions. However, the detection of the whole glutamatergicneurotransmitter system with its various receptors did not take placebefore the 1970's and 1980's when numerous antagonists were developedor, as in the case of PCP and ketamine, were identified as antagonists.Finally, in the 1990's molecular biology provided the tools for theclassification of the glutamatergic receptors.

N-methyl-D-aspartate (NMDA) receptors are a subtype of ionotropicglutamate receptors that mediate excitatory synaptic transmission in thebrain. NMDA receptors are ubiquitously distributed throughout the brainand play a key role in synaptic plasticity, synaptogenesis,excitotoxicity, memory acquisition and learning. NMDA receptors aredistinct from other major subtypes of ionotropic glutamate receptors(AMPA and kainate receptors) in that they are blocked by Mg²⁺ at restingmembrane potentials, are highly Ca²⁺ permeable, and requireco-activation by two distinct neurotransmitters: glutamate and glycine(or D-serine) (Traynelis S F et al., Pharmacol Rev. 2010; 62(3):405-96).The influx of Ca²⁺ through NMDA receptors triggers signaling cascadesand regulates gene expression that is critical for different forms ofsynaptic plasticity including both long-term potentiation of synapseefficacy (LTP) (Berberich S et al., Neuropharmacology 2007; 52(1):77-86)and long-term depression (LTD) (Massey, P V et al., J Neurosci. 2004Sep. 8; 24(36):7821-8).

The vast majority of the mammalian NMDA receptors form a heterotetramermade of two obligatory GluN1 units and two variable GluN2 receptorsubunits encoded by the GRIN1 gene and one of four GRIN2 genes,respectively. One or both GluN2 subunits can be potentially replaced bya GluN3A or a GluN3B subunit. The GRIN1 gene product has 8 splicevariants while there are 4 different GRIN2 genes (GRIN2A-D) encodingfour distinct GluN2 subunits. The glycine binding site is present on theGluN1 subunit and the glutamate binding site is present on the GluN2subunit.

The GluNR2 subunits play a dominant role in determining the functionaland pharmacological properties of the NMDA receptor assembly and exhibitdistinct distribution in different areas of the brain. For instance,GluN2B subunits are expressed primarily in the forebrain in the adultmammalian brain (Paoletti P et al., Nat Rev Neurosci. 2013;14(6):383-400; Watanabe M et al., J Comp Neurol. 1993; 338(3):377-90)and are implicated in learning, memory processing, mood, attention,emotion and pain perception (Cull-Candy S et al., Curr Opin Neurobiol.2001; 11(3):327-35).

Compounds that modulate GluN2B-containing NMDA receptor function can beuseful in treatment of many neurological and psychiatric disordersincluding but not limited to bipolar disorder (Martucci L et al.,Schizophrenia Res, 2006; 84(2-3):214-21), major depressive disorder(Miller O H et al., eLife. 2014; 3:e03581; Li N et al., Biol Psychiatry.2011; 69(8):754-61), treatment-resistant depression (Preskorn S H et al.J Clin Psychopharmacol. 2008; 28(6):631-7) and ther mood disorders(including schizophrenia (Grimwood S et al., Neuroreport. 1999;10(3):461-5; Weickert C S et al. Molecular Psychiatry (2013) 18,1185-1192), ante- and postpartum depression, seasonal affective disorderand the like), Alzheimer's disease (Hanson J E et al., Neurobiol Dis.2015; 74:254-62; Li S et al., J Neurosci. 2011; 31(18):6627-38) andother dementias (Orgogozo J M et al. Stroke 2002, 33: 1834-1839),Parkinson's disease (Duty S, CNS Drugs. 2012; 26(12):1017-32;Steece-Collier K et al., Exp Neurol. 2000; 163(1):239-43; Leaver K R etal. Clin Exp Pharmacol Physiol. 2008; 35(11):1388-94), Huntington'schorea (Tang T S et al., Proc Natl Acad Sci USA. 2005; 102(7):2602-7; LiL et al., J Neuro physiol. 2004; 92(5):2738-46), multiple sclerosis(Grasselli G et al., Br J Pharmacol. 2013; 168(2):502-17; Farjam M etal., Iran J Pharm Res. 2014; 13(2):695-705), cognitive impairment (WangD et al. 2014, Expert Opin Ther Targets Expert Opin Ther Targets. 2014;18(10):1121-30), head injury (Bullock M R et al., Ann N Y Acad Sci.1999; 890:51-8), spinal cord injury, stroke (Yang Y et al., J Neurosurg.2003; 98(2):397-403), epilepsy (Naspolini A P et al., Epilepsy Res. 2012June; 100(1-2):12-9), movement disorders (e.g. dyskinesias) (MorissetteM et al., Mov Disord. 2006; 21(1):9-17), various neurodegenerativediseases (e.g. amyotrophic lateral sclerosis (Fuller P I et al.,Neurosci Lett. 2006; 399(1-2):157-61) or neurodegeneration associatedwith bacterial or chronic infections), glaucoma (Naskar R et al. SeminOphthalmol. 1999 September; 14(3):152-8), pain (e.g. chronic, cancer,post-operative and neuropathic pain (Wu L J and Zhuo M,Neurotherapeutics. 2009; 6(4):693-702), diabetic neuropathy, migraine(Peeters M et al., J Pharmacol Exp Ther. 2007; 321(2):564-72), cerebralischemia (Yuan H et al., Neuron. 2015; 85(6):1305-18), encephalitis(Dalmau J. et al., Lancet Neurol. 2008; 7(12):1091-8.), autism andautism spectrum disorders (Won H. et al., Nature. 2012;486(7402):261-5), memory and learning disorders (Tang, Y. P. et al.,Nature. 1999; 401(6748):63-9), obsessive compulsive disorder (Arnold P Det al., Psychiatry Res. 2009; 172(2):136-9.), attention deficithyperactivity disorder (ADHD) (Dorval K M et al., Genes Brain Behav.2007; 6(5):444-52), PTSD (Haller J et al. Behav Pharmacol. 2011;22(2):113-21; Leaderbrand K et al. Neurobiol Learn Mem. 2014;113:35-40), tinnitus (Guitton M J, and Dudai Y, Neural Plast. 2007;80904; Hu S S et al. 2016; 273(2): 325-332), sleep disorders (likenarcolepsy or excessive daytime sleepiness, patent WO 2009058261 A1),vertigo and nystagmus (Straube A. et al., Curr Opin Neurol. 2005;18(1):11-4; Starck M et al. J Neurol. 1997 January; 244(1):9-16),anxiety autoimmunological disorders like neuropsychiatric systemic lupuserythematosus (Kowal C et al. Proc. Natl. Acad. Sci. U.S.A. 2006; 103,19854-19859) and addictive illnesses (e.g. alcohol addiction, drugaddiction) (Nagy J, 2004, Curr Drug Targets CNS Neurol Disord 2004;3(3):169-79.; Shen H et al., Proc Natl Acad Sci USA. 2011;108(48):19407-12).

In view of the clinical importance of GluN2B, the identification ofcompounds that modulate GluN2B receptor function represents anattractive avenue into the development of new therapeutic agents. Suchcompounds are provided herein.

SUMMARY OF THE INVENTION

The invention is directed to the general and preferred embodimentsdefined, respectively, by the independent and dependent claims appendedhereto, which are incorporated by reference herein. One aspect of thisinvention concerns compounds of Formula (I):

wherein

R¹ is H, halo, or CH₃;

Ar¹ is selected from the group consisting of:

-   -   (a) phenyl;    -   (b) phenyl substituted with one member selected from the group        consisting of: halo, C₁₋₆alkyl, C₁₋₆perhaloalkyl, and        OC₁₋₆perhaloalkyl;    -   (c) phenyl substituted with two or three members each        independently selected from the group consisting of: halo,        C₁₋₆alkyl, C₁₋₆perhaloalkyl, and OC₁₋₆perhaloalkyl; and    -   (d) thienyl substituted with one member selected from the group        consisting of: halo, and C₁₋₆alkyl;

R² is selected from the group consisting of:

-   -   (e)

R^(a) wherein R is selected from the group consisting of: C₁₋₆alkyl;C₃₋₆cycloalkyl; thienyl; pyridyl; pyridyl substituted with one or two Fmembers; pyrazinyl;

wherein R^(b) is C₁₋₆alkyl;

-   -   (f) C₁₋₆alkyl substituted with one, two, or three members each        independently selected from the group consisting of: OH, halo,        OC₁₋₆alkyl, (═N—OH), (═N—OCH₃), and cyclopropyl; and    -   (g) oxetanyl; oxetanyl substituted with C₁₋₆alkyl;        tetrahydrofuranyl; oxazolidinone; oxazolidinone substituted with        C₁₋₄alkyl, or cyclopropyl; and pyrrolidinone substituted with        C₁₋₄alkyl;        and pharmaceutically acceptable salts, stereoisomers, isotopic        variants, N-oxides, or solvates of compounds of Formula (I).

Further embodiments are provided by pharmaceutically acceptable salts ofcompounds of Formulas (I), pharmaceutically acceptable prodrugs ofcompounds of Formula (I), and pharmaceutically active metabolites ofcompounds of Formula (I).

In certain embodiments, the compounds of Formula (I) are compoundsselected from those species described or exemplified in the detaileddescription below.

In a further aspect, the invention relates to enantiomers anddiastereomers of the compounds of Formula (I), as well as thepharmaceutically acceptable salts.

In a further aspect, the invention relates to pharmaceuticalcompositions for treating a disease, disorder, or medical conditionmediated by GluN2B receptor activity, comprising an effective amount ofat least one compound selected from compounds of Formula (I),pharmaceutically acceptable salts of compounds of Formula (I),pharmaceutically acceptable prodrugs of compounds of Formula (I), andpharmaceutically active metabolites of Formula (I).

Pharmaceutical compositions according to the invention may furthercomprise one or more pharmaceutically acceptable excipients.

In another aspect, the chemical embodiments of the present invention areuseful as GluN2B receptor modulators. Thus, the invention is directed toa method for modulating GluN2B receptor activity, including when suchreceptor is in a subject, comprising exposing GluN2B receptor to aneffective amount of at least one compound selected from compounds ofFormula (I), pharmaceutically acceptable salts of compounds of Formula(I), pharmaceutically acceptable prodrugs of compounds of Formula (I),and pharmaceutically active metabolites of compounds of Formula (I).

In another aspect, the invention is directed to a method of treating asubject suffering from, or diagnosed with a disease, disorder, ormedical condition mediated by GluN2B receptor activity, comprisingadministering to the subject in need of such treatment an effectiveamount of at least one compound selected from compounds of Formula (I),pharmaceutically acceptable salts of compounds of Formula (I),pharmaceutically acceptable prodrugs of compounds of Formula (I), andpharmaceutically active metabolites of compounds of Formula (I).Additional embodiments of methods of treatment are set forth in thedetailed description.

In another aspect, the method of studying isotopically labeled compoundsin metabolic studies (preferably with ¹⁴C), reaction kinetic studies(with, for example ²H or ³H), detection or imaging techniques [such aspositron emission tomography (PET) or single-photon emission computedtomography (SPECT)] including drug or substrate tissue distributionassays, or in radioactive treatment of patients. For example, an ¹⁸F or¹¹C labeled compound may be particularly preferred for PET or SPECTstudies.

Additional embodiments of this invention include methods of makingcompounds of Formula (I), pharmaceutically acceptable salts of compoundsof Formula (I), pharmaceutically acceptable prodrugs of compounds ofFormula (I), and pharmaceutically active metabolites of Formula (I).

An object of the present invention is to overcome or ameliorate at leastone of the disadvantages of the conventional methodologies and/or priorart, or to provide a useful alternative thereto.

Additional embodiments, features, and advantages of the invention willbe apparent from the following detailed description and through practiceof the invention.

DETAILED DESCRIPTION OF INVENTION

In one aspect, provided herein are compounds of Formula (I),

wherein

R¹ is H, halo, or CH₃;

Ar¹ is selected from the group consisting of:

-   -   (a) phenyl;    -   (b) phenyl substituted with one member selected from the group        consisting of: halo, C₁₋₆alkyl, C₁₋₆perhaloalkyl, and        OC₁₋₆perhaloalkyl;    -   (c) phenyl substituted with two or three members each        independently selected from the group consisting of: halo,        C₁₋₆alkyl, C₁₋₆perhaloalkyl, and OC₁₋₆perhaloalkyl; and    -   (d) thienyl substituted with one member selected from the group        consisting of: halo, and C₁₋₆alkyl;

R² is selected from the group consisting of:

-   -   (e)

R^(a) wherein R is selected from the group consisting of: C₁₋₆alkyl;C₃₋₆cycloalkyl; thienyl; pyridyl; pyridyl substituted with one or two Fmembers; pyrazinyl;

wherein R is C₁₋₆alkyl;

-   -   (f) C₁₋₆alkyl substituted with one, two, or three members each        independently selected from the group consisting of: OH, halo,        OC₁₋₆alkyl, (═N—OH), (═N—OCH₃), and cyclopropyl; and    -   (g) oxetanyl; oxetanyl substituted with C₁₋₆alkyl;        tetrahydrofuranyl; oxazolidinone; oxazolidinone substituted with        C₁₋₄alkyl, or cyclopropyl; and pyrrolidinone substituted with        C₁₋₄alkyl;        and pharmaceutically acceptable salts, stereoisomers, isotopic        variants, N-oxides, or solvates thereof.        An additional embodiment of the invention is a compound of        Formula (I) wherein R¹ is H.        An additional embodiment of the invention is a compound of        Formula (I) wherein R¹ is F.        An additional embodiment of the invention is a compound of        Formula (I) wherein R¹ is CH₃.        An additional embodiment of the invention is a compound of        Formula (I) wherein Ar¹ is phenyl.        An additional embodiment of the invention is a compound of        Formula (I) wherein Ar¹ is phenyl substituted with one member        selected from the group consisting of: F, CH₃, CF₂H, CF₂CH₃,        CF₃, and OCF₃.        An additional embodiment of the invention is a compound of        Formula (I) wherein Ar¹ is selected from the group consisting        of:

An additional embodiment of the invention is a compound of Formula (I)wherein Ar¹ is phenyl substituted with two members each independentlyselected from the group consisting of: F, Cl, CH₃, CF₂H, CF₃, CF₂CH₃,and OCF₂H.An additional embodiment of the invention is a compound of Formula (I)wherein Ar¹ is selected from the group consisting of:

An additional embodiment of the invention is a compound of Formula (I)wherein Ar¹ is phenyl substituted with three members each independentlyselected from the group consisting of: F and CH₃.An additional embodiment of the invention is a compound of Formula (I)wherein Ar¹ is

An additional embodiment of the invention is a compound of Formula (I)wherein Ar¹ is thienyl is substituted with Cl or CH₃.An additional embodiment of the invention is a compound of Formula (I)wherein Ar¹ is

An additional embodiment of the invention is a compound of Formula (I)wherein R² is

An additional embodiment of the invention is a compound of Formula (I)wherein R² is

An additional embodiment of the invention is a compound of Formula (I)wherein R² is

An additional embodiment of the invention is a compound of Formula (I)wherein R² is

An additional embodiment of the invention is a compound of Formula (I)having the Formula (IA):

wherein

-   -   HAL is F or Cl;    -   R¹ is H, F, or CH₃;    -   R² is selected from the group consisting of:    -   (a) (S═O)CH₂CH₃; (SO₂)CH₂CH₃; or

wherein R^(a) is selected from the group consisting of: CH₃, CH₂CH₃,CH(CH₃)₂, cyclopropyl, cyclobutyl,

-   -   (b) CH₂OCH₃, CH(OH)(CH₂CH₃), CH(OH)CH(CH₃)₂, CF₂CH₂CH₃,        CF₂(cyclopropyl), CH(OCH₃)(cyclopropyl), CH(OH)(cyclopropyl), or

and

-   -   R^(c) is H, F or CH₃;    -   R^(d) is selected from the group consisting of: H, F, Cl, CH₃,        CF₂H, CF₂CH₃, CF₃, and OCF₂H; and    -   R^(e) is H or F; wherein when R^(e) is F, R^(c) is H.        An additional embodiment of the invention is a compound of        Formula (I) having the Formula (IA), wherein HAL is F; R¹ is H;        R^(c) is H; and R^(e) is H.    -   An additional embodiment of the invention is a compound of        Formula (I) having the Formula (IB)

wherein

-   -   Ar¹ is selected from the group consisting of:        -   (a) phenyl, 3-methylphenyl, 2-fluorophenyl, 3-fluorophenyl,            3-(difluoromethyl)phenyl, 3-(1,1-difluoroethyl)phenyl,            3-(trifluoromethyl)phenyl, 3-(trifluoromethoxy)phenyl,            5-methyl-2-thienyl, or 5-chloro-2-thienyl; and        -   (b) 2-fluoro-3-methyl-phenyl, 2,3-difluorophenyl,            3,5-difluorophenyl, 3-chloro-2-fluoro-phenyl,            2-fluoro-3-(trifluoromethyl)phenyl,            4-chloro-3-(difluoromethoxy)phenyl, or            4-chloro-3-(trifluoromethyl)phenyl; and R² is selected from            the group consisting of: (S═O)CH₂CH₃, (C═O)CH₂CH₃,            (C═O)CH(CH₃)₂, and (C═O)cyclopropyl.            A further embodiment of the current invention is a compound            as shown below in Table 1.

Ex # Compound Name 11-[6-(3,5-Difluorophenyl)pyrazol[4,3-b]pyridin-1-yl]butan-2-one 23-Methyl-1-[6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]butan-2-one; 3(RS)-3-Methyl-1-[6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]butan-2-ol; 41-[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]butan-2-one; 5(RS)-1-[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]butan-2-ol; 6(E/Z)-3-Methyl-1-[6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]butan-2-one oxime; 71-[6-(4-Fluoro-3-methyl-phenyl)pyrazolo[4,3-b]pyridin-1-yl]-3-methyl-butan-2-one; 8(RS)-1-[6-(4-Fluoro-3-methyl-phenyl)pyrazolo[4,3-b]pyridin-1-yl]-3-methyl-butan-2-ol; 91-Cyclopropyl-2-[6-(3,4,5-trifluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]ethanone; 10(RS)-1-Cyclopropyl-2-[6-(3,4,5-trifluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]ethanol; 11 (RS)-1-(2-Cyclopropyl-2-methoxy-ethyl)-6-(3,4,5-trifluorophenyl)pyrazolo[4,3-b]pyridine; 12(RS)-6-[3-(Difluoromethoxy)-4-fluoro-phenyl]-1-(ethylsulfinylmethyl)pyrazolo[4,3-b]pyridine; 136-[3-(Difluoromethoxy)-4-fluoro-phenyl]-1-(ethylsulfonylmethyl)pyrazolo[4,3-b]pyridine; 142-[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1-(2-pyridyl)ethanone; 152-(6-(3-(Difluoromethyl)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)-1-(5-fluoropyridin-2-yl)ethan-1-one; 162-(6-(3-(Difluoromethyl)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)-1-(pyridin-3-yl)ethan-1-one; 17(RS)-1-(Oxetan-2-ylmethyl)-6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridine; 18(RS)-6-[3-(Difluoromethyl)-4-fluoro-phenyl]-1-(tetrahydrofuran-2-ylmethyl)pyrazolo[4,3-b]pyridine; 19(RS)-4-[[6-[3-(Difluoromethoxy)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-1-methyl-pyrrolidin-2-one; 20(RS)-5-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]oxazolidin-2-one; 21(S)-5-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]oxazolidin-2-one; 22(R)-5-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]oxazolidin-2-one; 231-[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]propan-2-one; 241-[6-(4-Fluoro-3-methyl-phenyl)pyrazolo[4,3-b]pyridin-1-yl]propan-2-one;25 1-[6-[3-(Difluoromethoxy)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]propan-2-one; 261-[6-[4-Chloro-3-(difluoromethoxy)phenyl]pyrazolo[4,3-b]pyridin-1-yl]propan-2-one; 271-[6-(5-Chloro-2-thienyl)pyrazolo[4,3-b]pyridin-1-yl]butan-2-one; 281-[6-(4-Fluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]butan-2-one; 291-[6-(3-Fluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]butan-2-one; 301-[6-[3-(Difluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]butan-2-one;311-[6-[3-(1,1-Difluoroethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]butan-2-one; 321-[6-(4-Fluoro-3-methyl-phenyl)pyrazolo[4,3-b]pyridin-1-yl]butan-2-one;33 1-[6-(2,3-Difluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]butan-2-one; 341-[6-(3,4-Difluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]butan-2-one; 351-[6-(3,4-Difluorophenyl)-3-fluoro-pyrazolo[4,3-b]pyridin-1-yl]butan-2-one; 361-(6-(3-(Difluoromethyl)-4-fluorophenyl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-1-yl)butan-2-one; 371-[6-[3-(1,1-Difluoroethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]butan-2-one; 381-[6-[2-Fluoro-3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]butan-2-one; 391-[6-[4-Fluoro-3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]butan-2-one; 401-[6-[3-(Difluoromethoxy)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]butan-2-one; 411-[6-[4-Chloro-3-(difluoromethoxy)phenyl]pyrazolo[4,3-b]pyridin-1-yl]butan-2-one; 421-[6-(3,4,5-Trifluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]butan-2-one; 431-[6-(2,3,4-Trifluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]butan-2-one; 443-Methyl-1-(6-phenylpyrazolo[4,3-b]pyridin-1-yl)butan-2-one; 451-[6-(4-Fluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]-3-methyl-butan-2-one;461-[6-(3-Fluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]-3-methyl-butan-2-one;47 1-[6-[3-(Difluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]-3-methyl-butan-2-one; 481-[6-(2,3-Difluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]-3-methyl-butan-2-one; 491-[6-(3,4-Difluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]-3-methyl-butan-2-one; 501-[6-[2-Fluoro-3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]-3-methyl-butan-2-one; 511-[6-[4-Fluoro-3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]-3-methyl-butan-2-one; 521-[6-(4-Fluoro-2-methyl-phenyl)pyrazolo[4,3-b]pyridin-1-yl]-3-methyl-butan-2-one; 533-Methyl-1-[6-(3,4,5-trifluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]butan-2-one; 543-Methyl-1-[6-(2,3,4-trifluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]butan-2-one; 552-[6-(5-Chloro-2-thienyl)pyrazolo[4,3-b]pyridin-1-yl]-1-cyclopropyl-ethanone; 561-Cyclopropyl-2-[6-(5-methyl-2-thienyl)pyrazolo[4,3-b]pyridin-1-yl]ethanone; 571-Cyclopropyl-2-[6-(3-fluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]ethanone;581-Cyclopropyl-2-[6-(2-fluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]ethanone;591-Cyclopropyl-2-[6-(4-fluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]ethanone;60 1-Cyclopropyl-2-[6-(m-tolyl)pyrazolo[4,3-b]pyridin-1-yl]ethanone; 611-Cyclopropyl-2-[6-[3-(difluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]ethanone; 621-Cyclopropyl-2-[6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]ethanone; 631-Cyclopropyl-2-[6-[3-(trifluoromethoxy)phenyl]pyrazolo[4,3-b]pyridin-1-yl]ethanone; 641-Cyclopropyl-2-[6-(2,3-difluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]ethanone; 651-Cyclopropyl-2-[6-(3,4-difluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]ethanone; 661-Cyclopropyl-2-[6-(3,5-difluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]ethanone; 672-[6-(3-Chloro-2-fluoro-phenyl)pyrazolo[4,3-b]pyridin-1-yl]-1-cyclopropyl-ethanone; 682-[6-[3-Chloro-4-fluoro-phenyl)pyrazolo[4,3-b]pyridin-1-yl]-1-cyclopropyl-ethanone; 691-Cyclopropyl-2-[6-(4-fluoro-3-methyl-phenyl)pyrazolo[4,3-b]pyridin-1-yl]ethanone; 701-Cyclobutyl-2-[6-(4-fluoro-3-methyl-phenyl)pyrazolo[4,3-b]pyridin-1-yl]ethanone; 711-Cyclopropyl-2-[6-(2-fluoro-3-methyl-phenyl)pyrazolo[4,3-b]pyridin-1-yl]ethanone; 721-Cyclopropyl-2-[6-(4-fluoro-2-methyl-phenyl)pyrazolo[4,3-b]pyridin-1-yl]ethanone; 731-Cyclopropyl-2-[6-[2-fluoro-3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]ethanone; 741-Cyclopropyl-2-[6-[4-fluoro-3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]ethanone; 752-[6-[4-Chloro-3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1-cyclopropyl-ethanone; 761-Cyclopropyl-2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]ethanone; 771-Cyclopropyl-2-[6-[3-(difluoromethoxy)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]ethanone; 781-Cyclopropyl-2-[6-(4-fluoro-2,3-dimethyl-phenyl)pyrazolo[4,3-b]pyridin-1-yl]ethanone; 791-Cyclopropyl-2-[6-(2,3,4-trifluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]ethanone; 80(RS)-1-(Ethylsulfinylmethyl)-6-(3-fluorophenyl)pyrazolo[4,3-b]pyridine;81(RS)-1-(Ethylsulfinylmethyl)-6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridine; 82 (RS)6-(3,4-Difluorophenyl)-1-(ethylsulfinylmethyl)pyrazolo[4,3- b]pyridine;83(RS)-6-(3-(Difluoromethyl)-4-fluorophenyl)-1-((ethylsulfinyl)methyl)-1H-pyrazolo[4,3-b]pyridine; 84(S*)-6-(3-(Difluoromethyl)-4-fluorophenyl)-1-((ethylsulfinyl)methyl)-1H-pyrazolo[4,3-b]pyridine; 85(R*)-6-(3-(Difluoromethyl)-4-fluorophenyl)-1-((ethylsulfinyl)methyl)-1H-pyrazolo[4,3-b]pyridine; 86 (RS)-1-(Ethylsulfinylmethyl)-6-[2-fluoro-3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridine; 87(RS)-6-[4-Chloro-3-(difluoromethoxy)phenyl]-1-(ethylsulfinylmethyl)pyrazolo[4,3-b]pyridine; 88(RS)-1-(Ethylsulfinylmethyl)-6-(3,4,5-trifluorophenyl)pyrazolo[4,3-b]pyridine; 896-(4-Fluoro-3-methyl-phenyl)-1-(2-methoxyethyl)pyrazolo[4,3-b]pyridine;90(RS)-4-Methoxy-1-[6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]butan-2-ol; 91(RS)-1-[6-(3,4-Difluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]butan-2-ol; 92(RS)-1-[6-[3-(Difluoromethoxy)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]butan-2-ol; 93(RS)-1-[6-[4-Chloro-3-(difluoromethoxy)phenyl]pyrazolo[4,3-b]pyridin-1-yl]butan-2-ol; 94(RS)-1-[6-(3,4-Difluorophenyl)-3-fluoro-pyrazolo[4,3-b]pyridin-1-yl]butan-2-ol; 95(RS)-1-[6-[3-(1,1-Difluoroethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]butan-2-ol; 96(RS)-3-Methyl-1-(6-phenylpyrazolo[4,3-b]pyridin-1-yl)butan-2-ol; 97(RS)-3-Methyl-1-[6-(3,4,5-trifluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]butan-2-ol; 981-(2,2-Difluorobutyl)-6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridine; 99 1-(2,2-Difluorobutyl)-6-[3-(difluoromethoxy)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridine; 100(RS)-1-Cyclopropyl-2-[6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]ethanol; 101(RS)-1-Cyclopropyl-2-[6-(4-fluoro-3-methyl-phenyl)pyrazolo[4,3-b]pyridin-1-yl]ethanol; 102(R)-1-Cyclopropyl-2-[6-(4-fluoro-3-methyl-phenyl)pyrazolo[4,3-b]pyridin-1-yl]ethanol; 103(S)-1-Cyclopropyl-2-[6-(4-fluoro-3-methyl-phenyl)pyrazolo[4,3-b]pyridin-1-yl]ethanol; 104(RS)-1-Cyclopropyl-2-(6-(3-(difluoromethyl)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)ethan-1-ol; 105(E/Z)-N-Methoxy-3-methyl-1-[6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]butan-2-imine; 106(E/Z)-1-Cyclopropyl-2-[6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]ethanone oxime; 107(E/Z)-1-Cyclopropyl-2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]ethanone oxime; 1081-(2-Cyclopropyl-2,2-difluoro-ethyl)-6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridine; 1091-(2-Cyclopropyl-2,2-difluoro-ethyl)-6-[3-(difluoromethoxy)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridine; 1106-[3-(Difluoromethyl)-4-fluoro-phenyl]-1-[(3-methyloxetan-3-yl)methyl]pyrazolo[4,3-b]pyridine; 111(RS)-1-(Tetrahydrofuran-2-ylmethyl)-6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridine; 112(RS)-6-[3-(Difluoromethoxy)-4-fluoro-phenyl]-1-(tetrahydrofuran-2-ylmethyl)pyrazolo[4,3-b]pyridine; 113(RS)-6-[3-(Difluoromethyl)-4-fluoro-phenyl]-1-(tetrahydrofuran-3-ylmethyl)pyrazolo[4,3-b]pyridine; 114(RS)-5-((6-(3-(Difluoromethoxy)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)methyl)-1-methylpyrrolidin-2-one; 115(RS)-5-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-1-methyl-pyrrolidin-2-one; 116(RS)-3-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-1-methyl-pyrrolidin-2-one; 117(S)-3-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-1-methyl-pyrrolidin-2-one; 118(R)-3-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-1-methyl-pyrrolidin-2-one; 119(RS)-3-((6-(3-(Difluoromethoxy)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)methyl)-1-methylpyrrolidin-2-one; 120(RS)-4-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-1-methyl-pyrrolidin-2-one; 121(S)-4-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-1-methyl-pyrrolidin-2-one; 122(R)-4-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-1-methyl-pyrrolidin-2-one; 123(RS)-4-((6-(3-(difluoromethoxy)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)methyl)-3-methyloxazolidin-2-one; 124(RS)-4-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-3-methyl-oxazolidin-2-one; 125(RS)-5-[[6-[3-(Difluoromethoxy)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]oxazolidin-2-one; 126(RS)-5-[[6-[4-Chloro-3-(difluoromethoxy)phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]oxazolidin-2-one; 127(RS)-5-[[6-[3-(1,1-Difluoroethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]oxazolidin-2-one; 128(RS)-5-((6-(3-(Difluoromethoxy)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)methyl)-3-methyloxazolidin-2-one; 129(5R)-5-[[643-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-3-methyl-oxazolidin-2-one; 130(5S)-5-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-3-methyl-oxazolidin-2-one; 131(RS)-5-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-3-ethyl-oxazolidin-2-one; 132(S)-5-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-3-ethyl-oxazolidin-2-one; 133(R)-5-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-3-ethyl-oxazolidin-2-one; 134(RS)-3-Cyclopropyl-5-[[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]oxazolidin-2-one; 135(S)-3-Cyclopropyl-5-[[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]oxazolidin-2-one; 136(R)-3-Cyclopropyl-5-[[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]oxazolidin-2-one; 1372-[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1-(2-thienyl)ethanone; 1382-[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1-(3-thienyl)ethanone; 1392-[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1-(4-pyridyl)ethanone; 1402-(6-(3-(Difluoromethyl)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)-1-(3-fluoropyridin-2-yl)ethan-1-one; 1412-(6-(3-(Difluoromethyl)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)-1-(3,5-difluoropyridin-2-yl)ethan-1-one; and 1422-(6-(3-(Difluoromethyl)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)-1-(pyrazin-2-yl)ethan-1-one;and pharmaceutically acceptable salts, N-oxides, or solvates thereof.

-   -   A further embodiment of the current invention is a compound        selected from the group consisting of:

-   1-[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1l-yl]butan-2-one;

-   1-[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1l-yl]propan-2-one;

-   1-[6-(3,4-Difluorophenyl)pyrazolo[4,3-b]pyridin-1l-yl]butan-2-one;

-   1-(6-(3-(Difluoromethyl)-4-fluorophenyl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-1-yl)butan-2-one;

-   1-[6-[3-(Difluoromethoxy)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1l-yl]butan-2-one;

-   1-Cyclopropyl-2-[6-(4-fluorophenyl)pyrazolo[4,3-b]pyridin-1l-yl]ethanone;

-   1-Cyclopropyl-2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]ethanone;

-   (RS)-6-(3-(Difluoromethyl)-4-fluorophenyl)-1-((ethylsulfinyl)methyl)-1H-pyrazolo[4,3-b]pyridine;

-   (S*)-6-(3-(Difluoromethyl)-4-fluorophenyl)-1-((ethylsulfinyl)methyl)-1H-pyrazolo[4,3-b]pyridine;    and

-   (5R)-5-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-3-methyl-oxazolidin-2-one;    -   and pharmaceutically acceptable salts, solvates, stereoisomers,        isotopic variants, or N-oxides thereof.        An additional embodiment of the invention is a pharmaceutical        composition comprising:    -   (A) an effective amount of at least one compound selected from        compounds of Formula (I):

wherein

-   -   R¹ is H, halo, or CH₃;    -   Ar¹ is selected from the group consisting of:        -   (a) phenyl;        -   (b) phenyl substituted with one member selected from the            group consisting of: halo, C₁₋₆alkyl, C₁₋₆perhaloalkyl, and            OC₁₋₆perhaloalkyl;        -   (c) phenyl substituted with two or three members each            independently selected from the group consisting of: halo,            C₁₋₆alkyl, C₁₋₆perhaloalkyl, and OC₁₋₆perhaloalkyl; and        -   (d) thienyl substituted with one member selected from the            group consisting of: halo, and C₁₋₆alkyl;    -   R² is selected from the group consisting of:        -   (e)

R^(a) wherein R is selected from the group consisting of: C₁₋₆alkyl;C₃₋₆cycloalkyl; thienyl; pyridyl; pyridyl substituted with one or two Fmembers; pyrazinyl;

wherein R is C₁₋₆alkyl;

-   -   (f) C₁₋₆alkyl substituted with one, two, or three members each        independently selected from the group consisting of OH, halo,        OC₁₋₆alkyl, (═N—OH), (═N—OCH₃), and cyclopropyl; and    -   (g) oxetanyl; oxetanyl substituted with C₁₋₆alkyl;        tetrahydrofuranyl; oxazolidinone; oxazolidinone substituted with        C₁₋₄alkyl, or cyclopropyl; and pyrrolidinone substituted with        C₁₋₄alkyl;        and pharmaceutically acceptable salts, stereoisomers, isotopic        variants, N-oxides or solvates of compounds of Formula (I);

and (B) at least one pharmaceutically acceptable excipient.

An additional embodiment of the invention is a pharmaceuticalcomposition comprising and effective amount of at least one compound ofFormula (IA), as well as pharmaceutically acceptable salts, N-oxides orsolvates of compounds of Formula (IA), pharmaceutically acceptableprodrugs of compounds of Formula (IA), and pharmaceutically activemetabolites of Formula (IA); and at least one pharmaceuticallyacceptable excipient.

An additional embodiment of the invention is a pharmaceuticalcomposition comprising and effective amount of at least one compound ofFormula (IB), as well as pharmaceutically acceptable salts, N-oxides orsolvates of compounds of Formula (IB), pharmaceutically acceptableprodrugs of compounds of Formula (IB), and pharmaceutically activemetabolites of Formula (IB); and at least one pharmaceuticallyacceptable excipient.

An additional embodiment of the invention is a pharmaceuticalcomposition comprising and effective amount of at least one compound inTable 1, as well as pharmaceutically acceptable salts, N-oxides orsolvates of compounds of Table 1, pharmaceutically acceptable prodrugsof compounds of Table 1, and pharmaceutically active metabolites ofTable 1; and at least one pharmaceutically acceptable excipient.

Also within the scope of the invention are enantiomers and diastereomersof the compounds of Formula (I) (as well as Formulas (IA), and (IB)).Also within the scope of the invention are the pharmaceuticallyacceptable salts, N-oxides or solvates of the compounds of Formula (I)(as well as Formulas (IA), and (IB)). Also within the scope of theinvention are the pharmaceutically acceptable prodrugs of compounds ofFormula (I) (as well as Formulas (IA), and (IB)), and pharmaceuticallyactive metabolites of the compounds of Formula (I) (as well as Formulas(IA), and (IB)).

Also within the scope of the invention are isotopic variations ofcompounds of Formula (I) (as well as Formulas (IA), and (IB)), such as,e.g., deuterated compounds of Formula (I). Also within the scope of theinvention are the pharmaceutically acceptable salts, N-oxides orsolvates of the isotopic variations of the compounds of Formula (I) (aswell as Formulas (IA), and (IB)). Also within the scope of the inventionare the pharmaceutically acceptable prodrugs of the isotopic variationsof the compounds of Formula (I) (as well as Formulas (IA), and (IB)),and pharmaceutically active metabolites of the isotopic variations ofthe compounds of Formula (I) (as well as Formulas (IA), and (IB)).

An additional embodiment of the invention is a method of treating asubject suffering from or diagnosed with a disease, disorder, or medicalcondition mediated by GluN2B receptor activity, comprising administeringto a subject in need of such treatment an effective amount of at leastone compound selected from compounds of Formula (I):

wherein

-   -   R¹ is H, halo, or CH₃;    -   Ar¹ is selected from the group consisting of:        -   (a) phenyl;        -   (b) phenyl substituted with one member selected from the            group consisting of: halo, C₁₋₆alkyl, C₁₋₆perhaloalkyl, and            OC₁₋₆perhaloalkyl;        -   (c) phenyl substituted with two or three members each            independently selected from the group consisting of: halo,            C₁₋₆alkyl, C₁₋₆perhaloalkyl, and OC₁₋₆perhaloalkyl; and        -   (d) thienyl substituted with one member selected from the            group consisting of: halo, and C₁₋₆alkyl;    -   R² is selected from the group consisting of:        -   (e)

wherein R^(a) is selected from the group consisting of: C₁₋₆alkyl;C₃₋₆cycloalkyl; thienyl; pyridyl; pyridyl substituted with one or two Fmembers; pyrazinyl

wherein R^(b) is C₁₋₆alkyl;

-   -   -   (f) C₁₋₆alkyl substituted with one, two, or three members            each independently selected from the group consisting of:            OH, halo, OC₁₋₆alkyl, (═N—OH), (═N—OCH₃), and cyclopropyl;            and        -   (g) oxetanyl; oxetanyl substituted with C₁₋₆alkyl;            tetrahydrofuranyl; oxazolidinone; oxazolidinone substituted            with C₁₋₄alkyl, or cyclopropyl; and pyrrolidinone            substituted with C₁₋₄alkyl;            and pharmaceutically acceptable salts, stereoisomers,            isotopic variants, N-oxides, or solvates thereof, to a            subject in need thereof.

An additional embodiment of the invention is a method of treating asubject suffering from or diagnosed with a disease, disorder, or medicalcondition mediated by GluN2B receptor activity, comprising administeringto a subject in need of such treatment an effective amount of at leastone compound selected from compounds of Formula (I) (as well as Formulas(IA), and (IB)), enantiomers and diastereomers of the compounds ofFormula (I), isotopic variations of the compounds of Formula (I), andpharmaceutically acceptable salts of all of the foregoing.

In preferred embodiments of the inventive method, the disease, disorder,or medical condition is selected from: neurologic and psychiatricdisorders including, but not limited to: (1) mood disorders and moodaffective disorders; (2) neurotic, stress-related and somatoformdisorders including anxiety disorders; (3) disorders of psychologicaldevelopment; (4) behavioral syndromes associated with physiologicaldisturbances and physical factors; (5) extrapyramidal and movementdisorders; (6) episodic and paroxysmal disorders, epilepsy; (7) pain;(8) forms of neurodegeneration; (9) cerebrovascular diseases, acute andchronic; and any sequelae of cerebrovascular diseases.

Examples of mood disorders and mood affective disorders that can betreated according to the present invention include, but are not limitedto, bipolar disorder I depressed, hypomanic, manic and mixed form;bipolar disorder II; depressive disorders, such as single depressiveepisode or recurrent major depressive disorder, minor depressivedisorder, treatment-resistant depression, depressive disorder withpostpartum onset, depressive disorders with psychotic symptoms;persistent mood disorders, such as cyclothymia, dysthymia, euthymia; andpremenstrual dysphoric disorder.

Examples of disorders belonging to the neurotic, stress-related andsomatoform disorders that can be treated according to the presentinvention include, but are not limited to, anxiety disorders, generalanxiety disorder, panic disorder with or without agoraphobia, specificphobia, social anxiety disorder, chronic anxiety disorders; obsessivecompulsive disorder; reaction to sever stress and adjustment disorders,such as post-traumatic stress disorder (PTSD); other neurotic disorderssuch as depersonalisation-derealisation syndrome.

Examples of disorders of psychological development that can be treatedaccording to the present invention include, but are not limited topervasive developmental disorders, including but not limited toAsperger's syndrome and Rett's syndrome, autistic disorders, childhoodautism and overactive disorder associated with mental retardation andstereotyped movements, specific developmental disorder of motorfunction, specific developmental disorders of scholastic skills.

Examples of behavioral syndromes associated with physiologicaldisturbances and physical factors according to the present inventioninclude but are not limited to mental and behavioral disordersassociated with childbirth, including but not limited to postnatal(postpartum) and prenatal depression; eating disorders, including butnot limited to anorexia nervosa, bulimia nervosa, pica and binge eatingdisorder.

Examples of extrapyramidal and movement disorders that can be treatedaccording to the present invention include, but are not limited toParkinson's disease; second Parkinsonism, such as post encephaliticParkinsonism; Parkinsonism comprised in other disorders; Lewis bodydisease; degenerative diseases of the basal ganglia; otherextrapyramidal and movement disorders including but not limited totremor, essential tremor and drug-induced tremor, myoclonus, chorea anddrug-induced chorea, drug-induced tics and tics of organic origin,drug-induced acute dystonia, drug-induced tardive dyskinesia,L-dopa-induced dyskinesia; neuroleptic-induced movement disordersincluding but not limited to neuroleptic malignant syndrome (NMS),neuroleptic induced parkinsonism, neuroleptic-induced early onset oracute dyskinesia, neuroleptic-induced acute dystonia,neuroleptic-induced acute akathisia, neuroleptic-induced tardivedyskinesia, neuroleptic-induced tremor; restless leg syndrome, Stiff-mansyndrome.

Further examples of movement disorders with malfunction and/ordegeneration of basal ganglia that can be treated according to thepresent invention include but are not limited to dystonia including butnot limited to focal dystonia, multiple-focal or segmental dystonia,torsion dystonia, hemispheric, generalised and tardive dystonia (inducedby psychopharmacological drugs). Focal dystonia includes cervicaldystonia (torticolli), blepharospasm (cramp of the eyelid), appendiculardystonia (cramp in the extremities, like the writer's cramp),oromandibular dystonia and spasmodic dysphonia (cramp of the vocalcord);

Examples for episodic and paroxysmal disorders that can be treatedaccording to the present invention include, but are not limited toepilepsy, including localization-related (focal)(partial) idiopathicepilepsy and epileptic syndromes with seizures of localized onset,localization-related (focal)(partial) symptomatic epilepsy and epilepticsyndromes with simple partial seizures, localization-related(focal)(partial) symptomatic epilepsy and epileptic syndromes withcomplex partial seizures, generalized idiopathic epilepsy and epilepticsyndromes including but not limited to myoclonic epilepsy in infancy,neonatal convulsions (familial), childhood absence epilepsy(pyknolepsy), epilepsy with grand mal seizures on awakening, absenceepilepsy, myoclonic epilepsy (impulsive petit mal) and nonspecificatonic, clonic, myoclonic, tonic, tonic-clonic epileptic seizures.

Further examples of epilepsy that can be treated according to thepresent invention include, but are not limited to epilepsy withmyoclonic absences, myoclonic-astatic seizures, infantile spasms,Lennox-Gastaut syndrome, Salaam attacks, symptomatic early myoclonicencephalopathy, West's syndrome, petit and grand mal seizures; statusepilepticus.

Examples of pain include, but are not limited to pain disorders relatedto psychological factors, such as persistent somatoform disorders;acute, chronic and chronic intractable pain, headache; acute and chronicpain related to physiological processes and physical disorders includingbut not limited to back pain, tooth pain, abdominal pain, low back pain,pain in joints; acute and chronic pain that is related to diseases ofthe musculoskeletal system and connective tissue including, but notlimited to rheumatism, myalgia, neuralgia and fibromyalgia; acute andchronic pain that is related to nerve, nerve root and plexus disorders,such as trigeminal pain, postzoster neuralgia, phantom limb syndromewith pain, carpal tunnel syndrome, lesion of sciatic nerve, diabeticmononeuropathy; acute and chronic pain that is related topolyneuropathies and other disorders of the peripheral nervous system,such as hereditary and idiopathic neuropathy, inflammatorypolyneuropathy, polyneuropathy induced by drugs, alcohol or toxicagents, polyneuropathy in neoplastic disease, diabetic polyneuropathy.

Examples of diseases that include forms of neurodegeneration include,but are not limited to, acute neurodegeneration, such as intracranialbrain injuries, such as stroke, diffuse and local brain injuries,epidural, subdural and subarachnoid haemorrhage, and chronicneurodegeneration, such as Alzheimer's disease, Huntington's disease,multiple sclerosis and ALS.

Examples of cerebrovascular diseases include, but are not limited to,subarachnoid haemorrhage, intracerebral haemorrhage and othernontraumatic intracranial haemorrhage, cerebral infarction, stroke,occlusion and stenosis or precerebral and cerebral arteries, notresulting in cerebral infarction, dissection of cerebral arteries,cerebral aneurysm, cerebral atherosclerosis, progressive vascularleukoencephalopathy, hypertensive encephalopathy, nonpyogenic thrombosisof intracranial venous system, cerebral arteritis, cerebral amyloidangiopathy and sequelae of cerebrovascular diseases.

In some embodiments, administration of a compound of the invention, orpharmaceutically acceptable salt thereof, is effective in preventing thedisease; for example, preventing a disease, condition or disorder in anindividual who may be predisposed to the disease, condition or disorderbut does not yet experience or display the pathology or symptomatologyof the disease.

Additional embodiments, features, and advantages of the invention willbe apparent from the following detailed description and through practiceof the invention.

The invention may be more fully appreciated by reference to thefollowing description, including the following glossary of terms and theconcluding examples. For the sake of brevity, the disclosures of thepublications, including patents, cited in this specification are hereinincorporated by reference.

As used herein, the terms “including”, “containing” and “comprising” areused herein in their open, non-limiting sense.

The term “alkyl” refers to a straight- or branched-chain alkyl grouphaving from 1 to 12 carbon atoms in the chain. Examples of alkyl groupsinclude methyl (Me, which also may be structurally depicted by thesymbol, “/”), ethyl (Et), n-propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl (tBu), pentyl, isopentyl, tert-pentyl, hexyl,isohexyl, and groups that in light of the ordinary skill in the art andthe teachings provided herein would be considered equivalent to any oneof the foregoing examples. The term C₁₋₄alkyl as used here refers to astraight- or branched-chain alkyl group having from 1 to 4 carbon atomsin the chain. The term C₁₋₆alkyl as used here refers to a straight- orbranched-chain alkyl group having from 1 to 6 carbon atoms in the chain.

The term “aryl” refers to a monocyclic, aromatic carbocycle (ringstructure having ring atoms that are all carbon) having 6 atoms perring. (Carbon atoms in the aryl groups are sp² hybridized.)

The term “phenyl” represents the following moiety:

The term “thienyl” represents the following moiety:

The term “heteroaryl” refers to a monocyclic or fused bicyclicheterocycle (ring structure having ring atoms selected from carbon atomsand up to four heteroatoms selected from nitrogen, oxygen, and sulfur)having from 3 to 9 ring atoms per heterocycle. Illustrative examples ofheteroaryl groups include the following entities, in the form ofproperly bonded moieties:

Those skilled in the art will recognize that the species of heteroaryl,cycloalkyl, aryl and heterocycloalkyl groups listed or illustrated aboveare not exhaustive, and that additional species within the scope ofthese defined terms may also be selected.

A “heterocycloalkyl” refers to a monocyclic ring structure that issaturated or partially saturated and has from 4 to 7 ring atoms per ringstructure selected from carbon atoms and up to two heteroatoms selectedfrom nitrogen, oxygen, and sulfur. The ring structure may optionallycontain up to two oxo groups on sulfur ring members. Illustrativeentities, in the form of properly bonded moieties, include:

The term “cycloalkyl” refers to a saturated or partially saturated,monocyclic, fused polycyclic, or spiro polycyclic carbocycle having from3 to 12 ring atoms per carbocycle. Illustrative examples of cycloalkylgroups include the following entities, in the form of properly bondedmoieties:

The term “halo” represents chloro, fluoro, bromo or iodo.

The term “perhaloalkyl” or “haloalkyl” refers to a straight- orbranched-chain alkyl group having from 1 to 6 carbon atoms in the chainoptionally substituting hydrogens with halogens. The term“C₁₋₄haloalkyl” as used here refers to a straight- or branched-chainalkyl group having from 1 to 4 carbon atoms in the chain, optionallysubstituting hydrogens with halogens. The term “C₁₋₆haloalkyl” as usedhere refers to a straight- or branched-chain alkyl group having from 1to 6 carbon atoms in the chain, optionally substituting hydrogens withhalogens. Examples of “perhaloalkyl”, “haloalkyl” groups includetrifluoromethyl (CF₃), difluoromethyl (CF₂H), monofluoromethyl (CH₂F),pentafluoroethyl (CF₂CF₃), tetrafluoroethyl (CHFCF₃), monofluoroethyl(CH₂CH₂F), trifluoroethyl (CH₂CF₃), tetrafluorotrifluoromethylethyl(—CF(CF₃)₂), and groups that in light of the ordinary skill in the artand the teachings provided herein would be considered equivalent to anyone of the foregoing examples.

The term “substituted” means that the specified group or moiety bearsone or more substituents. The term “unsubstituted” means that thespecified group bears no substituents. The term “optionally substituted”means that the specified group is unsubstituted or substituted by one ormore substituents. Where the term “substituted” is used to describe astructural system, the substitution is meant to occur at anyvalency-allowed position on the system. In cases where a specifiedmoiety or group is not expressly noted as being optionally substitutedor substituted with any specified substituent, it is understood thatsuch a moiety or group is intended to be unsubstituted.

The terms “para”, “meta”, and “ortho” have the meanings as understood inthe art. Thus, for example, a fully substituted phenyl group hassubstituents at both “ortho” (o) positions adjacent to the point ofattachment of the phenyl ring, both “meta” (m) positions, and the one“para” (p) position across from the point of attachment. To furtherclarify the position of substituents on the phenyl ring, the 2 differentortho positions will be designated as ortho and ortho′ and the 2different meta positions as meta and meta′ as illustrated below.

When referring to substituents on a pyridyl group, the terms “para”,“meta”, and “ortho” refer to the placement of a substituent relative tothe point of attachment of the pyridyl ring. For example the structurebelow is described as 3-pyridyl with the X¹ substituent in the orthoposition, the X² substituent in the meta position, and X³ substituent inthe para position:

To provide a more concise description, some of the quantitativeexpressions given herein are not qualified with the term “about”. It isunderstood that, whether the term “about” is used explicitly or not,every quantity given herein is meant to refer to the actual given value,and it is also meant to refer to the approximation to such given valuethat would reasonably be inferred based on the ordinary skill in theart, including equivalents and approximations due to the experimentaland/or measurement conditions for such given value. Whenever a yield isgiven as a percentage, such yield refers to a mass of the entity forwhich the yield is given with respect to the maximum amount of the sameentity that could be obtained under the particular stoichiometricconditions. Concentrations that are given as percentages refer to massratios, unless indicated differently.

The terms “buffered” solution or “buffer” solution are used hereininterchangeably according to their standard meaning. Buffered solutionsare used to control the pH of a medium, and their choice, use, andfunction is known to those of ordinary skill in the art. See, forexample, G. D. Considine, ed., Van Nostrand's Encyclopedia of Chemistry,p. 261, 5^(th) ed. (2005), describing, inter alia, buffer solutions andhow the concentrations of the buffer constituents relate to the pH ofthe buffer. For example, a buffered solution is obtained by adding MgSO₄and NaHCO₃ to a solution in a 10:1 w/w ratio to maintain the pH of thesolution at about 7.5.

Any formula given herein is intended to represent compounds havingstructures depicted by the structural formula as well as certainvariations or forms. In particular, compounds of any formula givenherein may have asymmetric centers and therefore exist in differentenantiomeric forms. All optical isomers of the compounds of the generalformula, and mixtures thereof, are considered within the scope of theformula. Thus, any formula given herein is intended to represent aracemate, one or more enantiomeric forms, one or more diastereomericforms, one or more atropisomeric forms, and mixtures thereof.Furthermore, certain structures may exist as geometric isomers (i.e.,cis and trans isomers), as tautomers, or as atropisomers.

It is also to be understood that compounds that have the same molecularformula but differ in the nature or sequence of bonding of their atomsor the arrangement of their atoms in space are termed “isomers.” Isomersthat differ in the arrangement of their atoms in space are termed “.”

Stereoisomers that are not mirror images of one another are termed“diastereomers” and those that are non-superimposable mirror images ofeach other are termed “enantiomers.” When a compound has an asymmetriccenter, for example, it is bonded to four different groups, and a pairof enantiomers is possible. An enantiomer can be characterized by theabsolute configuration of its asymmetric center and is described by theR- and S-sequencing rules of Cahn and Prelog, or by the manner in whichthe molecule rotates the plane of polarized light and designated asdextrorotatory or levorotatory (i.e., as (+)- or (−)-isomersrespectively). A chiral compound can exist as either an individualenantiomer or as a mixture thereof. A mixture containing equalproportions of the enantiomers is called a “racemic mixture.”

“Tautomers” refer to compounds that are interchangeable forms of aparticular compound structure, and that vary in the displacement ofhydrogen atoms and electrons. Thus, two structures may be in equilibriumthrough the movement of 7 electrons and an atom (usually H).

For example, enols and ketones are tautomers because they are rapidlyinterconverted by treatment with either acid or base. Another example oftautomerism is the aci- and nitro-forms of phenyl nitromethane, that arelikewise formed by treatment with acid or base.

Tautomeric forms may be relevant to the attainment of the optimalchemical reactivity and biological activity of a compound of interest.

The compounds of this invention may possess one or more asymmetriccenters; such compounds can therefore be produced as individual (R)- or(S)-stereoisomers or as mixtures thereof.

Unless indicated otherwise, the description or naming of a particularcompound in the specification and claims is intended to include bothindividual enantiomers and mixtures, racemic or otherwise, thereof. Themethods for the determination of stereochemistry and the separation ofstereoisomers are well-known in the art.

Certain examples contain chemical structures that are depicted as anabsolute enantiomer but are intended to indicate enantiopure materialthat is of unknown configuration. In these cases (R*) or (S*) is used inthe name to indicate that the absolute stereochemistry of thecorresponding stereocenter is unknown. Thus, a compound designated as(R*) refers to an enantiopure compound with an absolute configuration ofeither (R) or (S). In cases where the absolute stereochemistry has beenconfirmed, the structures are named using (R) and (S).

The symbols

and

are used as meaning the same spatial arrangement in chemical structuresshown herein. Analogously, the symbols

and

are used as meaning the same spatial arrangement in chemical structuresshown herein.

Additionally, any formula given herein is intended to refer also tohydrates, solvates, and polymorphs of such compounds, and mixturesthereof, even if such forms are not listed explicitly. Certain compoundsof Formula (I) (as well as Formulas (IA), and (IB)), or pharmaceuticallyacceptable salts of compounds of Formula (I) (as well as Formulas (IA),and (IB)) may be obtained as solvates. Solvates include those formedfrom the interaction or complexation of compounds of the invention withone or more solvents, either in solution or as a solid or crystallineform. In some embodiments, the solvent is water and the solvates arehydrates. In addition, certain crystalline forms of compounds of Formula(I) (as well as Formulas (IA), and (IB)) or pharmaceutically acceptablesalts of compounds of Formula (I) (as well as Formulas (IA), and (IB))may be obtained as co-crystals. In certain embodiments of the invention,compounds of Formula (I) were obtained in a crystalline form. In otherembodiments, crystalline forms of compounds of Formula (I) were cubic innature. In other embodiments, pharmaceutically acceptable salts ofcompounds of Formula (I) were obtained in a crystalline form. In stillother embodiments, compounds of Formula (I) were obtained in one ofseveral polymorphic forms, as a mixture of crystalline forms, as apolymorphic form, or as an amorphous form. In other embodiments,compounds of Formula (I) convert in solution between one or morecrystalline forms and/or polymorphic forms.

Reference to a compound herein stands for a reference to any one of: (a)the actually recited form of such compound, and (b) any of the forms ofsuch compound in the medium in which the compound is being consideredwhen named. For example, reference herein to a compound such as R—COOH,encompasses reference to any one of, for example, R—COOH_((s)),R—COOH_((so1)), and R—COO⁻ _((sol)). In this example, R—COOH_((s))refers to the solid compound, as it could be for example in a tablet orsome other solid pharmaceutical composition or preparation;R—COOH_((sol)) refers to the undissociated form of the compound in asolvent; and R—COO⁻ _((sol)) refers to the dissociated form of thecompound in a solvent, such as the dissociated form of the compound inan aqueous environment, whether such dissociated form derives fromR—COOH, from a salt thereof, or from any other entity that yields R—COO⁻upon dissociation in the medium being considered. In another example, anexpression such as “exposing an entity to compound of formula R—COOH”refers to the exposure of such entity to the form, or forms, of thecompound R—COOH that exists, or exist, in the medium in which suchexposure takes place. In still another example, an expression such as“reacting an entity with a compound of formula R—COOH” refers to thereacting of (a) such entity in the chemically relevant form, or forms,of such entity that exists, or exist, in the medium in which suchreacting takes place, with (b) the chemically relevant form, or forms,of the compound R—COOH that exists, or exist, in the medium in whichsuch reacting takes place. In this regard, if such entity is for examplein an aqueous environment, it is understood that the compound R—COOH isin such same medium, and therefore the entity is being exposed tospecies such as R—COOH_((aq)) and/or R—COO⁻ _((aq)), where the subscript“(aq)” stands for “aqueous” according to its conventional meaning inchemistry and biochemistry. A carboxylic acid functional group has beenchosen in these nomenclature examples; this choice is not intended,however, as a limitation but it is merely an illustration. It isunderstood that analogous examples can be provided in terms of otherfunctional groups, including but not limited to hydroxyl, basic nitrogenmembers, such as those in amines, and any other group that interacts ortransforms according to known manners in the medium that contains thecompound. Such interactions and transformations include, but are notlimited to, dissociation, association, tautomerism, solvolysis,including hydrolysis, solvation, including hydration, protonation, anddeprotonation. No further examples in this regard are provided hereinbecause these interactions and transformations in a given medium areknown by any one of ordinary skill in the art.

In another example, a zwitterionic compound is encompassed herein byreferring to a compound that is known to form a zwitterion, even if itis not explicitly named in its zwitterionic form. Terms such aszwitterion, zwitterions, and their synonyms zwitterionic compound(s) arestandard IUPAC-endorsed names that are well known and part of standardsets of defined scientific names. In this regard, the name zwitterion isassigned the name identification CHEBI:27369 by the Chemical Entities ofBiological Interest (ChEBI) dictionary of molecular entities. Asgenerally well known, a zwitterion or zwitterionic compound is a neutralcompound that has formal unit charges of opposite sign. Sometimes thesecompounds are referred to by the term “inner salts”. Other sources referto these compounds as “dipolar ions”, although the latter term isregarded by still other sources as a misnomer. As a specific example,aminoethanoic acid (the amino acid glycine) has the formula H₂NCH₂COOH,and it exists in some media (in this case in neutral media) in the formof the zwitterion ⁺H₃NCH₂COO⁻. Zwitterions, zwitterionic compounds,inner salts and dipolar ions in the known and well established meaningsof these terms are within the scope of this invention, as would in anycase be so appreciated by those of ordinary skill in the art. Becausethere is no need to name each and every embodiment that would berecognized by those of ordinary skill in the art, no structures of thezwitterionic compounds that are associated with the compounds of thisinvention are given explicitly herein. They are, however, part of theembodiments of this invention. No further examples in this regard areprovided herein because the interactions and transformations in a givenmedium that lead to the various forms of a given compound are known byany one of ordinary skill in the art.

Any formula given herein is also intended to represent unlabeled formsas well as isotopically labeled forms of the compounds. Isotopicallylabeled compounds have structures depicted by the formulas given hereinexcept that one or more atoms are replaced by an atom having a selectedatomic mass or mass number. Examples of isotopes that can beincorporated into compounds of the invention include isotopes ofhydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine,chlorine, and iodine such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O ³¹P,³²P, ³⁵S, ¹⁸F, ³⁶Cl, ¹²⁵I, respectively. Such isotopically labeledcompounds are useful in metabolic studies (preferably with ¹⁴C),reaction kinetic studies (with, for example deuterium (i.e., D or ²H);or tritium (i.e., T or ³H)), detection or imaging techniques [such aspositron emission tomography (PET) or single-photon emission computedtomography (SPECT)] including drug or substrate tissue distributionassays, or in radioactive treatment of patients. In particular, an ¹⁸For ¹¹C labeled compound may be particularly preferred for PET or SPECTstudies. Further, substitution with heavier isotopes such as deuterium(i.e., ²H) may afford certain therapeutic advantages resulting fromgreater metabolic stability, for example increased in vivo half-life orreduced dosage requirements. Isotopically labeled compounds of thisinvention and prodrugs thereof can generally be prepared by carrying outthe procedures disclosed in the schemes or in the examples andpreparations described below by substituting a readily availableisotopically labeled reagent for a non-isotopically labeled reagent.

When referring to any formula given herein, the selection of aparticular moiety from a list of possible species for a specifiedvariable is not intended to define the same choice of the species forthe variable appearing elsewhere. In other words, where a variableappears more than once, the choice of the species from a specified listis independent of the choice of the species for the same variableelsewhere in the formula, unless stated otherwise.

According to the foregoing interpretive considerations on assignmentsand nomenclature, it is understood that explicit reference herein to aset implies, where chemically meaningful and unless indicated otherwise,independent reference to embodiments of such set, and reference to eachand every one of the possible embodiments of subsets of the set referredto explicitly.

By way of a first example on substituent terminology, if substituent S¹_(example) is one of S₁ and S₂, and substituent S² _(example) is one ofS₃ and S₄, then these assignments refer to embodiments of this inventiongiven according to the choices S¹ _(example) is S₁ and S² _(example) isS₃; S¹ _(example) is S₁ and S² _(example) is S₄; S¹ _(example) is S₂ andS² _(example) is S₃; S¹ _(example) is S₂ and S² _(example) is S₄; andequivalents of each one of such choices. The shorter terminology “S¹_(example) is one of S₁ and S₂, and S² _(example) is one of S₃ and S₄”is accordingly used herein for the sake of brevity, but not by way oflimitation. The foregoing first example on substituent terminology,which is stated in generic terms, is meant to illustrate the varioussubstituent assignments described herein. The foregoing convention givenherein for substituents extends, when applicable, to members such as R¹,Ar¹, R², R^(a), R^(b), R^(e), R^(d), R^(e), HAL, and X, and any othergeneric substituent symbol used herein.

Furthermore, when more than one assignment is given for any member orsubstituent, embodiments of this invention comprise the variousgroupings that can be made from the listed assignments, takenindependently, and equivalents thereof. By way of a second example onsubstituent terminology, if it is herein described that substituentS_(example) is one of S₁, S₂, and S₃, this listing refers to embodimentsof this invention for which S_(example) is S₁; S_(example) is S₂;S_(example) is S₃; S_(example) is one of S₁ and S₂; S_(example) is oneof S₁ and S₃; S_(example) is one of S₂ and S₃; S_(example) is one of S₁,S₂ and S₃; and S_(example) is any equivalent of each one of thesechoices. The shorter terminology “S_(example) is one of S₁, S₂, and S₃”is accordingly used herein for the sake of brevity, but not by way oflimitation. The foregoing second example on substituent terminology,which is stated in generic terms, is meant to illustrate the varioussubstituent assignments described herein. The foregoing convention givenherein for substituents extends, when applicable, to members such as R¹,Ar¹, R², R^(a), R^(b), R^(c), R^(d), R^(e), HAL, and X, and any othergeneric substituent symbol used herein.

The nomenclature “C_(i-j)” with j>i, when applied herein to a class ofsubstituents, is meant to refer to embodiments of this invention forwhich each and every one of the number of carbon members, from i to jincluding i and j, is independently realized. By way of example, theterm C₁₋₄ refers independently to embodiments that have one carbonmember (C₁), embodiments that have two carbon members (C₂), embodimentsthat have three carbon members (C₃), and embodiments that have fourcarbon members (C₄).

The term C_(n-m)alkyl refers to an aliphatic chain, whether straight orbranched, with a total number N of carbon members in the chain thatsatisfies n≤N≤m, with m>n. Any disubstituent referred to herein is meantto encompass the various attachment possibilities when more than one ofsuch possibilities are allowed. For example, reference to disubstituent-A-B-, where A≠B, refers herein to such disubstituent with A attached toa first substituted member and B attached to a second substitutedmember, and it also refers to such disubstituent with A attached to thesecond substituted member and B attached to the first substitutedmember.

The invention includes also pharmaceutically acceptable salts of thecompounds of Formula (I) (as well as Formulas (IA), and (IB)),preferably of those described above and of the specific compoundsexemplified herein, and methods of treatment using such salts.

The term “pharmaceutically acceptable” means approved or approvable by aregulatory agency of Federal or a state government or the correspondingagency in countries other than the United States, or that is listed inthe U. S. Pharmacopoeia or other generally recognized pharmacopoeia foruse in animals, and more particularly, in humans.

A “pharmaceutically acceptable salt” is intended to mean a salt of afree acid or base of compounds represented by Formula (I) (as well asFormulas (IA), and (IB)) that are non-toxic, biologically tolerable, orotherwise biologically suitable for administration to the subject. Itshould possess the desired pharmacological activity of the parentcompound. See, generally, G. S. Paulekuhn, et al., “Trends in ActivePharmaceutical Ingredient Salt Selection based on Analysis of the OrangeBook Database”, J. Med. Chem., 2007, 50:6665-72, S. M. Berge, et al.,“Pharmaceutical Salts”, J Pharm Sci., 1977, 66:1-19, and Handbook ofPharmaceutical Salts, Properties, Selection, and Use, Stahl and Wermuth,Eds., Wiley-VCH and VHCA, Zurich, 2002.

Examples of pharmaceutically acceptable salts are those that arepharmacologically effective and suitable for contact with the tissues ofpatients without undue toxicity, irritation, or allergic response. Acompound of Formula (I) (as well as Formulas (IA), and (IB)) may possessa sufficiently acidic group, a sufficiently basic group, or both typesof functional groups, and accordingly react with a number of inorganicor organic bases, and inorganic and organic acids, to form apharmaceutically acceptable salt.

Examples of pharmaceutically acceptable salts include sulfates,pyrosulfates, bisulfates, sulfites, bisulfites, phosphates,monohydrogen-phosphates, dihydrogenphosphates, metaphosphates,pyrophosphates, chlorides, bromides, iodides, acetates, propionates,decanoates, caprylates, acrylates, formates, isobutyrates, caproates,heptanoates, propiolates, oxalates, malonates, succinates, suberates,sebacates, fumarates, maleates, butyne-1,4-dioates, hexyne-1,6-dioates,benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates,hydroxybenzoates, methoxybenzoates, phthalates, sulfonates,xylenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates,citrates, lactates, γ-hydroxybutyrates, glycolates, tartrates,methane-sulfonates, propanesulfonates, naphthalene-1-sulfonates,naphthalene-2-sulfonates, and mandelates.

When the compounds of Formula (I) (as well as Formulas (IA), and (IB))contain a basic nitrogen, the desired pharmaceutically acceptable saltmay be prepared by any suitable method available in the art. Forexample, treatment of the free base with an inorganic acid, such ashydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid,nitric acid, boric acid, phosphoric acid, and the like, or with anorganic acid, such as acetic acid, phenylacetic acid, propionic acid,stearic acid, lactic acid, ascorbic acid, maleic acid, hydroxymaleicacid, isethionic acid, succinic acid, valeric acid, fumaric acid,malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid,oleic acid, palmitic acid, lauric acid, a pyranosidyl acid, such asglucuronic acid or galacturonic acid, an alpha-hydroxy acid, such asmandelic acid, citric acid, or tartaric acid, an amino acid, such asaspartic acid, glutaric acid or glutamic acid, an aromatic acid, such asbenzoic acid, 2-acetoxybenzoic acid, naphthoic acid, or cinnamic acid, asulfonic acid, such as laurylsulfonic acid, p-toluenesulfonic acid,methanesulfonic acid, ethanesulfonic acid, any compatible mixture ofacids such as those given as examples herein, and any other acid andmixture thereof that are regarded as equivalents or acceptablesubstitutes in light of the ordinary level of skill in this technology.

When the compound of Formula (I) (as well as Formulas (IA), and (IB)) isan acid, such as a carboxylic acid or sulfonic acid, the desiredpharmaceutically acceptable salt may be prepared by any suitable method,for example, treatment of the free acid with an inorganic or organicbase, such as an amine (primary, secondary or tertiary), an alkali metalhydroxide, alkaline earth metal hydroxide, any compatible mixture ofbases such as those given as examples herein, and any other base andmixture thereof that are regarded as equivalents or acceptablesubstitutes in light of the ordinary level of skill in this technology.Illustrative examples of suitable salts include organic salts derivedfrom amino acids, such as N-methyl-D-glucamine, lysine, choline, glycineand arginine, ammonia, carbonates, bicarbonates, primary, secondary, andtertiary amines, and cyclic amines, such as tromethamine, benzylamines,pyrrolidines, piperidine, morpholine, and piperazine, and inorganicsalts derived from sodium, calcium, potassium, magnesium, manganese,iron, copper, zinc, aluminum, and lithium.

The invention also relates to pharmaceutically acceptable prodrugs ofthe compounds of Formula (I) (as well as Formulas (IA), and (IB)), andtreatment methods employing such pharmaceutically acceptable prodrugs.The term “prodrug” means a precursor of a designated compound that,following administration to a subject, yields the compound in vivo via achemical or physiological process such as solvolysis or enzymaticcleavage, or under physiological conditions (e.g., a prodrug on beingbrought to physiological pH is converted to the compound of Formula (I).A “pharmaceutically acceptable prodrug” is a prodrug that is non-toxic,biologically tolerable, and otherwise biologically suitable foradministration to the subject. Illustrative procedures for the selectionand preparation of suitable prodrug derivatives are described, forexample, in “Design of Prodrugs”, ed. H. Bundgaard, Elsevier, 1985.

Exemplary prodrugs include compounds having an amino acid residue, or apolypeptide chain of two or more (e.g., two, three or four) amino acidresidues, covalently joined through an amide or ester bond to a freeamino, hydroxyl, or carboxylic acid group of a compound of Formula (I)(as well as Formulas (IA), and (IB)). Examples of amino acid residuesinclude the twenty naturally occurring amino acids, commonly designatedby three letter symbols, as well as 4-hydroxyproline, hydroxylysine,demosine, isodemosine, 3-methylhistidine, norvalin, beta-alanine,gamma-aminobutyric acid, citrulline homocysteine, homoserine, ornithineand methionine sulfone.

Additional types of prodrugs may be produced, for instance, byderivatizing free carboxyl groups of structures of Formula (I) (as wellas Formulas (IA), and (IB)) as amides or alkyl esters. Examples ofamides include those derived from ammonia, primary C₁₋₆alkyl amines andsecondary di(C₁₋₆alkyl) amines. Secondary amines include 5- or6-membered heterocycloalkyl or heteroaryl ring moieties. Examples ofamides include those that are derived from ammonia, C₁₋₃alkyl primaryamines, and di(C₁₋₂alkyl)amines. Examples of esters of the inventioninclude C₁₋₇alkyl, C₅₋₇cycloalkyl, phenyl, and phenyl(C₁₋₆alkyl) esters.Preferred esters include methyl esters. Prodrugs may also be prepared byderivatizing free hydroxy groups using groups including hemisuccinates,phosphate esters, dimethylaminoacetates, andphosphoryloxymethyloxycarbonyls, following procedures such as thoseoutlined in Fleisher et al., Adv. Drug Delivery Rev. 1996, 19, 115-130.Carbamate derivatives of hydroxy and amino groups may also yieldprodrugs. Carbonate derivatives, sulfonate esters, and sulfate esters ofhydroxy groups may also provide prodrugs. Derivatization of hydroxygroups as (acyloxy)methyl and (acyloxy)ethyl ethers, wherein the acylgroup may be an alkyl ester, optionally substituted with one or moreether, amine, or carboxylic acid functionalities, or where the acylgroup is an amino acid ester as described above, is also useful to yieldprodrugs. Prodrugs of this type may be prepared as described in Robinsonet al., J Med Chem. 1996, 39 (1), 10-18. Free amines can also bederivatized as amides, sulfonamides or phosphonamides. All of theseprodrug moieties may incorporate groups including ether, amine, andcarboxylic acid functionalities.

The present invention also relates to pharmaceutically activemetabolites of the compounds of Formula (I) (as well as Formulas (IA),and (IB)), which may also be used in the methods of the invention. A“pharmaceutically active metabolite” means a pharmacologically activeproduct of metabolism in the body of a compound of Formula (I) (as wellas Formulas (IA), and (IB)) as applicable, or salt thereof. Prodrugs andactive metabolites of a compound may be determined using routinetechniques known or available in the art. See, e.g., Bertolini, et al.,J Med Chem. 1997, 40, 2011-2016; Shan, et al., J Pharm Sci. 1997, 86(7), 765-767; Bagshawe, Drug DevRes. 1995, 34, 220-230; Bodor, AdvDrugRes. 1984, 13, 224-331; Bundgaard, Design of Prodrugs (Elsevier Press,1985); and Larsen, Design and Application of Prodrugs, Drug DesignandDevelopment (Krogsgaard-Larsen, et al., eds., Harwood AcademicPublishers, 1991).

The compounds of Formula (I) (as well as Formulas (IA), and (IB)) andtheir pharmaceutically acceptable salts, pharmaceutically acceptableprodrugs, and pharmaceutically active metabolites of the presentinvention are useful as modulators of the GluN2B receptor in the methodsof the invention. As such modulators, the compounds may act asantagonists, agonists, or inverse agonists. The term “modulators”include both inhibitors and activators, where “inhibitors” refer tocompounds that decrease, prevent, inactivate, desensitize, ordown-regulate the GluN2B receptor expression or activity, and“activators” are compounds that increase, activate, facilitate,sensitize, or up-regulate GluN2B receptor expression or activity.

The term “treat”, “treatment” or “treating”, as used herein, is intendedto refer to administration of an active agent or composition of theinvention to a subject for the purpose of affecting a therapeutic orprophylactic benefit through modulation of GluN2B receptor activity.

Treating includes reversing, ameliorating, alleviating, inhibiting theprogress of, lessening the severity of, or preventing a disease,disorder, or condition, or one or more symptoms of such disease,disorder or condition mediated through modulation of GluN2B receptoractivity. The term “subject” refers to a mammalian patient in need ofsuch treatment, such as a human.

Accordingly, the invention relates to methods of using the compoundsdescribed herein to treat subjects diagnosed with or suffering from adisease, disorder, or condition mediated by GluN2B receptor activity,such as: bipolar disorder I depressed, hypomanic, manic and mixed form;bipolar disorder II; depressive disorders, such as single depressiveepisode or recurrent major depressive disorder, minor depressivedisorder, treatment-resistant depression, depressive disorder withpostpartum onset, disruptive mood dysregulation disorder, depressivedisorders with psychotic symptoms; persistent mood disorders, such ascyclothymia, dysthymia, euthymia; and premenstrual dysphoric disorder;anxiety disorders, general anxiety disorder, panic disorder with orwithout agoraphobia, specific phobia, social anxiety disorder, chronicanxiety disorders; obsessive compulsive disorder; reaction to severstress and adjustment disorders, such as post-traumatic stress disorder(PTSD); other neurotic disorders such as depersonalization-derealisationsyndrome; pervasive developmental disorders, including but not limitedto Asperger's syndrome and Rett's syndrome, autistic disorders,childhood autism and overactive disorder associated with mentalretardation and stereotyped movements, specific developmental disorderof motor function, specific developmental disorders of scholasticskills; postnatal (postpartum) and prenatal depression; eatingdisorders, including but not limited to anorexia nervosa, bulimianervosa, pica and binge eating disorder; Parkinson's disease; secondParkinsonism, such as post encephalitic Parkinsonism; Parkinsonismcomprised in other disorders; Lewis body disease; degenerative diseasesof the basal ganglia; other extrapyramidal and movement disordersincluding but not limited to tremor, essential tremor and drug-inducedtremor, myoclonus, chorea and drug-induced chorea, drug-induced tics andtics of organic origin, drug-induced acute dystonia, drug-inducedtardive dyskinesia, L-dopa-induced dyskinesia; neuroleptic-inducedmovement disorders including but not limited to neuroleptic malignantsyndrome (NMS), neuroleptic induced parkinsonism, neuroleptic-inducedearly onset or acute dyskinesia, neuroleptic-induced acute dystonia,neuroleptic-induced acute akathisia, neuroleptic-induced tardivedyskinesia, neuroleptic-induced tremor; restless leg syndrome, Stiff-mansyndrome; dystonia including but not limited to focal dystonia,multiple-focal or segmental dystonia, torsion dystonia, hemispheric,generalized and tardive dystonia (induced by psychopharmacologicaldrugs). Focal dystonia include cervical dystonia (torticolli),blepharospasm (cramp of the eyelid), appendicular dystonia (cramp in theextremities, like the writer's cramp), oromandibular dystonia andspasmodic dysphonia (cramp of the vocal cord); epilepsy, includinglocalization-related (focal)(partial) idiopathic epilepsy and epilepticsyndromes with seizures of localized onset, localization-related(focal)(partial) symptomatic epilepsy and epileptic syndromes withsimple partial seizures, localization-related (focal)(partial)symptomatic epilepsy and epileptic syndromes with complex partialseizures, generalized idiopathic epilepsy and epileptic syndromesincluding but not limited to myoclonic epilepsy in infancy, neonatalconvulsions (familial), childhood absence epilepsy (pyknolepsy),epilepsy with grand mal seizures on awakening, absence epilepsy,myoclonic epilepsy (impulsive petit mal) and nonspecific atonic, clonic,myoclonic, tonic, tonic-clonic epileptic seizures; epilepsy withmyoclonic absences, myoclonic-astatic seizures, infantile spasms,Lennox-Gastaut syndrome, Salaam attacks, symptomatic early myoclonicencephalopathy, West's syndrome, petit and grand mal seizures; statusepilepticus; persistent somatoform disorders; acute, chronic and chronicintractable pain, headache; acute and chronic pain related tophysiological processes and physical disorders including but not limitedto back pain, tooth pain, abdominal pain, low back pain, pain in joints;acute and chronic pain that is related to diseases of themusculoskeletal system and connective tissue including, but not limitedto rheumatism, myalgia, neuralgia and fibromyalgia; acute and chronicpain that is related to nerve, nerve root and plexus disorders, such astrigeminal pain, postzoster neuralgia, phantom limb syndrome with pain,carpal tunnel syndrome, lesion of sciatic nerve, diabeticmononeuropathy; acute and chronic pain that is related topolyneuropathies and other disorders of the peripheral nervous system,such as hereditary and idiopathic neuropathy, inflammatorypolyneuropathy, polyneuropathy induced by drugs, alcohol or toxicagents, polyneuropathy in neoplastic disease, diabetic polyneuropathy;and acute neurodegeneration, such as intracranial brain injuries, suchas stroke, diffuse and local brain injuries, epidural, subdural andsubarachnoid haemorrhage, and chronic neurodegeneration, such asAlzheimer's disease, Huntington's disease, multiple sclerosis, and ALS;subarachnoid haemorrhage, intracerebral haemorrhage and othernontraumatic intracranial haemorrhage, cerebral infarction, stroke,occlusion and stenosis or precerebral and cerebral arteries, notresulting in cerebral infarction, dissection of cerebral arteries,cerebral aneurysm, cerebral atherosclerosis, progressive vascularleukoencephalopathy, hypertensive encephalopathy, nonpyogenic thrombosisof intracranial venous system, cerebral arteritis, cerebral amyloidangiopathy and sequelae of cerebrovascular diseases; glaucoma and otherneuropathies; dementias, vascular dementia, Lewy body dementia,frontotemporal dementia, and HIV-dementia; vertigo and nystagmus;tinnitus; neuropsychiatric systemic lupus erythematosus; disruptive mooddysregulation disorder; schizophrenia spectrum disorder; and sleep/wakedisorders.

In treatment methods according to the invention, an effective amount ofa pharmaceutical agent according to the invention is administered to asubject suffering from or diagnosed as having such a disease, disorder,or condition. An “effective amount” means an amount or dose sufficientto generally bring about the desired therapeutic or prophylactic benefitin patients in need of such treatment for the designated disease,disorder, or condition. Effective amounts or doses of the compounds ofthe present invention may be ascertained by routine methods such asmodeling, dose escalation studies or clinical trials, and by taking intoconsideration routine factors, e.g., the mode or route of administrationor drug delivery, the pharmacokinetics of the compound, the severity andcourse of the disease, disorder, or condition, the subject's previous orongoing therapy, the subject's health status and response to drugs, andthe judgment of the treating physician. An example of a dose is in therange of from about 0.001 to about 200 mg of compound per kg ofsubject's body weight per day, preferably about 0.05 to 100 mg/kg/day,or about 1 to 35 mg/kg/day, in single or divided dosage units (e.g.,BID, TID, QID). For a 70-kg human, an illustrative range for a suitabledosage amount is from about 0.05 to about 7 g/day, or about 0.2 to about2.5 g/day.

Once improvement of the patient's disease, disorder, or condition hasoccurred, the dose may be adjusted for preventative or maintenancetreatment. For example, the dosage or the frequency of administration,or both, may be reduced as a function of the symptoms, to a level atwhich the desired therapeutic or prophylactic effect is maintained. Ofcourse, if symptoms have been alleviated to an appropriate level,treatment may cease. Patients may, however, require intermittenttreatment on a long-term basis upon any recurrence of symptoms.

In addition, the active agents of the invention may be used incombination with additional active ingredients in the treatment of theabove conditions. The additional active ingredients may beco-administered separately with an active agent of compounds of Table 1or included with such an agent in a pharmaceutical composition accordingto the invention. In an exemplary embodiment, additional activeingredients are those that are known or discovered to be effective inthe treatment of conditions, disorders, or diseases mediated by GluN2Bactivity, such as another GluN2B modulator or a compound active againstanother target associated with the particular condition, disorder, ordisease. The combination may serve to increase efficacy (e.g., byincluding in the combination a compound potentiating the potency oreffectiveness of an active agent according to the invention), decreaseone or more side effects, or decrease the required dose of the activeagent according to the invention.

The active agents of the invention are used, alone or in combinationwith one or more additional active ingredients, to formulatepharmaceutical compositions of the invention. A pharmaceuticalcomposition of the invention comprises: (a) an effective amount of atleast one active agent in accordance with the invention; and (b) apharmaceutically acceptable excipient.

A “pharmaceutically acceptable excipient” refers to a substance that isnon-toxic, biologically tolerable, and otherwise biologically suitablefor administration to a subject, such as an inert substance, added to apharmacological composition or otherwise used as a vehicle, carrier, ordiluent to facilitate administration of an agent and that is compatibletherewith. Examples of excipients include calcium carbonate, calciumphosphate, various sugars and types of starch, cellulose derivatives,gelatin, vegetable oils, and polyethylene glycols.

Delivery forms of the pharmaceutical compositions containing one or moredosage units of the active agents may be prepared using suitablepharmaceutical excipients and compounding techniques known or thatbecome available to those skilled in the art. The compositions may beadministered in the inventive methods by a suitable route of delivery,e.g., oral, parenteral, rectal, topical, or ocular routes, or byinhalation.

The preparation may be in the form of tablets, capsules, sachets,dragees, powders, granules, lozenges, powders for reconstitution, liquidpreparations, or suppositories. Preferably, the compositions areformulated for intravenous infusion, topical administration, or oraladministration.

For oral administration, the compounds of the invention can be providedin the form of tablets or capsules, or as a solution, emulsion, orsuspension. To prepare the oral compositions, the compounds may beformulated to yield a dosage of, e.g., from about 0.05 to about 100mg/kg daily, or from about 0.05 to about 35 mg/kg daily, or from about0.1 to about 10 mg/kg daily. For example, a total daily dosage of about5 mg to 5 g daily may be accomplished by dosing once, twice, three, orfour times per day.

Oral tablets may include a compound according to the invention mixedwith pharmaceutically acceptable excipients such as inert diluents,disintegrating agents, binding agents, lubricating agents, sweeteningagents, flavoring agents, coloring agents and preservative agents.Suitable inert fillers include sodium and calcium carbonate, sodium andcalcium phosphate, lactose, starch, sugar, glucose, methyl cellulose,magnesium stearate, mannitol, sorbitol, and the like. Exemplary liquidoral excipients include ethanol, glycerol, water, and the like. Starch,polyvinyl-pyrrolidone (PVP), sodium starch glycolate, microcrystallinecellulose, and alginic acid are suitable disintegrating agents. Bindingagents may include starch and gelatin. The lubricating agent, ifpresent, may be magnesium stearate, stearic acid or talc. If desired,the tablets may be coated with a material such as glyceryl monostearateor glyceryl distearate to delay absorption in the gastrointestinal tractor may be coated with an enteric coating.

Capsules for oral administration include hard and soft gelatin capsules.To prepare hard gelatin capsules, compounds of the invention may bemixed with a solid, semi-solid, or liquid diluent. Soft gelatin capsulesmay be prepared by mixing the compound of the invention with water, anoil such as peanut oil or olive oil, liquid paraffin, a mixture of monoand di-glycerides of short chain fatty acids, polyethylene glycol 400,or propylene glycol.

Liquids for oral administration may be in the form of suspensions,solutions, emulsions or syrups or may be lyophilized or presented as adry product for reconstitution with water or other suitable vehiclebefore use. Such liquid compositions may optionally contain:pharmaceutically-acceptable excipients such as suspending agents (forexample, sorbitol, methyl cellulose, sodium alginate, gelatin,hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel andthe like); non-aqueous vehicles, e.g., oil (for example, almond oil orfractionated coconut oil), propylene glycol, ethyl alcohol, or water;preservatives (for example, methyl or propyl p-hydroxybenzoate or sorbicacid); wetting agents such as lecithin; and, if desired, flavoring orcoloring agents.

The active agents of this invention may also be administered by non-oralroutes. For example, the compositions may be formulated for rectaladministration as a suppository. For parenteral use, includingintravenous, intramuscular, intraperitoneal, or subcutaneous routes, thecompounds of the invention may be provided in sterile aqueous solutionsor suspensions, buffered to an appropriate pH and isotonicity or inparenterally acceptable oil. Suitable aqueous vehicles include Ringer'ssolution and isotonic sodium chloride. Such forms will be presented inunit-dose form such as ampules or disposable injection devices, inmulti-dose forms such as vials from which the appropriate dose may bewithdrawn, or in a solid form or pre-concentrate that can be used toprepare an injectable formulation. Illustrative infusion doses may rangefrom about 1 to 1000 μg/kg/minute of compound, admixed with apharmaceutical carrier over a period ranging from several minutes toseveral days.

For topical administration, the compounds may be mixed with apharmaceutical carrier at a concentration of about 0.1% to about 10% ofdrug to vehicle. Another mode of administering the compounds of theinvention may utilize a patch formulation to affect transdermaldelivery. Compounds of the invention may alternatively be administeredin methods of this invention by inhalation, via the nasal or oralroutes, e.g., in a spray formulation also containing a suitable carrier.

Exemplary compounds useful in methods of the invention will now bedescribed by reference to the illustrative synthetic schemes for theirgeneral preparation below and the specific examples that follow.Artisans will recognize that, to obtain the various compounds herein,starting materials may be suitably selected so that the ultimatelydesired substituents will be carried through the reaction scheme with orwithout protection as appropriate to yield the desired product.Alternatively, it may be necessary or desirable to employ, in the placeof the ultimately desired substituent, a suitable group that may becarried through the reaction scheme and replaced as appropriate with thedesired substituent. Unless otherwise specified, the variables are asdefined above in reference to Formula (I). Reactions may be performedbetween the melting point and the reflux temperature of the solvent, andpreferably between 0° C. and the reflux temperature of the solvent.Reactions may be heated employing conventional heating or microwaveheating. Reactions may also be conducted in sealed pressure vesselsabove the normal reflux temperature of the solvent.

Abbreviations and acronyms used herein include the following

TABLE 2 Term Acronym Aqueous aq Atmosphere atm tert-Butylcarbamoyl BocBroad br Diatomaceous Earth Celite ® Electrospray ionization ESINormal-phase silica gel chromatography FCC GluNR2B * GluN_(2B), NMDA-R2B, NR2B, hNR3 Grams g Hours h High-pressure liquid chromatography HPLCHertz Hz Isopropyl alcohol iPrOH, IPA Liquid chromatography and massspectrometry LCMS Molar M Mass to charge ratio m/z Milligrams mg Minutemin Milliliter mL Microliter μL Millimoles mmol Mass spectrometry MSNormal N Nuclear magnetic resonance NMR Parts per million ppmPrecipitate ppt Polytetrafluoroethylene PTFE Retention time R_(t) Roomtemperature rt Saturated sat Supercritical Fluid Chromatography SFCTemperature T Thin layer chromatography TLC Volume in milliliters ofsolvent per gram of substrate V, or volumes * (Collingridge, G. L, etal, Neuropharmacology, 2009, 56, 2-5)

PREPARATIVE EXAMPLES

Exemplary compounds useful in methods of the invention will now bedescribed by reference to the illustrative synthetic schemes for theirgeneral preparation below and the specific examples to follow.

According to SCHEME 1, commercially available or syntheticallyaccessible 6-bromo-1H-pyrrolo[3,2-b]pyridine is fluorinated with anelectrophilic halogen source under conditions known to one skilled inthe art. For example, 6-bromo-1H-pyrrolo[3,2-b]pyridine is fluorinatedusing a reagent such as N-fluoro-N′-(chloromethyl)triethylenediaminebis(tetrafluoroborate) (Selectfluor®) and the like; in a suitablesolvent such as acetonitrile (ACN), dichloromethane (DCM), and the like,at a temperature of 90° C., to provide6-Bromo-3-fluoro-1H-pyrazolo[4,3-b]pyridine.

According to SCHEME 2, a compound of formula (V), where R¹ iscyclobutyl, pyrizinyl, pyridyl, pyridyl substituted with one or two Fmembers is brominated using a reagent such as Br₂, HBr, pyridiniumtribromide, phenyltrimehtylammonium tribromide, and the like; in asuitable solvent such as methanol (MeOH), tetrahydrofuran (THF), aceticacid (AcOH), and the like; at temperatures ranging from 0° C. to 60° C.;to provide a compound of formula (VI).

According to SCHEME 3, a compound of formula (VII) where thehydroxymethyl group is attached at either of the carbon atoms asindicated with (*), is chlorinated using a reagent such as SOCl₂, andthe like; an amine base such as pyridine; in a solvent such as DCM, andthe like; at a temperature of 90° C.; to afford a compound of formula(VIII).

According to SCHEME 4, a compound of formula (IX) where R¹ is H, isalkylated with (chloromethyl)(ethyl)sulfane, a base such as Cs₂CO₃, andthe like; in a solvent such as DMF, and the like, at room temperature,for a period of 20 hours, to provide6-bromo-1-(ethylsulfanylmethyl)pyrazolo[4,3-b]pyridine and6-bromo-2-(ethylsulfanylmethyl)pyrazolo[4,3-b]pyridine.6-Bromo-1-(ethylsulfanylmethyl)pyrazolo[4,3-b]pyridine is oxidized usinga reagent such as meta-chloroperoxybenzoic acid (m-CPBA), and the like,in a suitable solvent such as DCM, and the like; at a temperature of 0°C.; to provide a 6-bromo-1-(ethylsulfinylmethyl)pyrazolo[4,3-b]pyridine.

According to SCHEME 5, a compound of formula (XII) is alkylatedemploying conditions previously described to provide a compound offormula (XIII). A compound of formula (XIII), where Ar¹ is3-(difluoromethoxy)-4-fluorophenyl, is oxidized using a reagent such asm-CPBA, in a solvent such as DCM, at room temperature, to provide acompound of formula (XIV). A compound of formula (XIV), where Ar¹ is3-(difluoromethoxy)-4-fluorophenyl, is reduced using a reagent such asPd/C (10%), in a solvent such as EtOH, EtOAc, or a mixture thereof, atroom temperature, to provide a compound of Formula (I).

According to SCHEME 6, a compound of formula (XVI), where Ar¹ is4-fluoro-3-methyl-phenyl and R³ is ethyl for example, is reacted withdiethylaminosulfur trifluoride (DAST), in a suitable solvent such asDCM, and the like, at a temperature of about 0° C. to room temperature,to provide a compound of formula (XVII)

According to SCHEME 7, a compound of Formula (I) is prepared in twosteps from a compound of formula (IX). In a first step, a compound offormula (IX), where R¹ is H, or CH₃, is reacted in a metal mediatedcross coupling reaction to provide a compound of formula (XVIII), whereAr¹ is a phenyl optionally substituted with one, two, or three memberseach independently selected from halo, C₁₋₆alkyl, C₁₋₆perhaloalkyl, andOC₁₋₆perhaloalkyl. For example, a compound of formula (IX), where R¹ isH, or CH₃, is reacted with a commercially available or syntheticallyaccessible suitably substituted aryl boronic acid, boronate ester, andthe like; in the presence of a palladium catalyst such asbis(triphenylphosphine)palladium(II)chloride (PdCl₂(PPh₃)₂),bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex withdichloromethane (PdCl₂(dppf).DCM),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)(PdCl₂(dppf)), tetrakis(triphenylphosphine)palladium(0) (Pd(PPh₃)₄),2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)methanesulfonate (RuPhos-Pd-G3), and the like; a base such as Na₂CO₃,Cs₂CO₃, and the like; in a suitable solvent such as ACN, water,1,4-dioxane, or a mixture thereof; at a temperature ranging from 70°C.-120° C.; for a period ranging from 2 h to 48 h, using conventional ormicrowave heating, to provide a compound of formula (XVIII).

In a second step, a compound of formula (XVIII), where R¹ is H or CH₃,and Ar¹ is a phenyl optionally substituted with one, two, or threemembers each independently selected from halo, C₁₋₆alkyl,C₁₋₆perhaloalkyl, and OC₁₋₆perhaloalkyl, is alkylated with a compound offormula (XIX), where X is Br or Cl, and R² is as described in claim 1;using a base such as N-ethyldiisopropylamine (DIEA, DIPEA), Cs₂CO₃,NaHC₃, NaH, and the like; an additive such as KI; in a solvent such asdimethylformamide (DMF), tetrahydrofuran (THF), acetonitrile (ACN), andthe like; at a temperature ranging from 0° C. to 80° C.; for a period ofup to 76 h; to provide a compound of Formula (I).

In an alternate method, a compound of Formula (I) is prepared in twosteps from a compound of formula (IX). In a first step, a compound offormula (IX) where R¹ is H, or F, is alkylated employing conditionspreviously described with an alkyl agent of formula (XIX), where X is Bror Cl, and R² is as described in claim 1, to provide a compound offormula (XX). In a second step, coupling with a suitably substitutedphenyl or thienyl boronic acid or ester, employing conditions previouslydescribed, provides a compound of Formula (I).

A compound of Formula (I), where R² is (C═O)C₁₋₆alkyl, is reduced with areducing agent such as NaBH₄, and the like; in a suitable solvent suchas MeOH, THF, or a mixture thereof, at a temperature ranging from 0° C.to rt; to provide a compound of Formula (I), where R² isCH(OH)C₁₋₆alkyl.

A compound of Formula (I), where R² is (C═O)C₁₋₆alkyl, is reacted with anucleophile such as hydroxylamine hydrochloride, o-methylhydroxylaminehydrochloride, and the like; using a base such as Cs₂CO₃, triethylamine,NaHCO₃, and the like; in a solvent such as MeOH, EtOH, H₂O, or a mixturethereof, to provide a compound of Formula (I), where R² isC(═N—OH)C₁₋₆alkyl, or C(═N—OCH₃)C₁₋₆alkyl.

A compound of Formula (I), where R² is (C═O)C₁₋₆alkyl, is fluorinatedunder conditions known to one skilled in the art, for example, reactionwith a fluorinated reagent such as DAST, bis(2-methoxyethyl)aminosulfurtrifluoride (Deoxo-Fluor®), and the like; in a solvent such as DCM, THF,and the like; at a temperature ranging from 0° C. to rt; to provide acompound of Formula (I), where R² is C(F₂)C₁₋₆alkyl.

A compound of Formula (I), where R² is CH(OH)C₁₋₆alkyl, is fluorinatedunder conditions known to one skilled in the art, for example, reactionwith a fluorinated reagent such as DAST, Deoxo-Fluor®, and the like; ina solvent such as DCM, THF, and the like; at a temperature ranging from0° C. to rt; to provide a compound of Formula (I), where R² isCH(F)C₁₋₆alkyl.

A compound of Formula (I), where R² is CH(OH)C₁₋₆alkyl is methylatedwith iodomethane; using a base such as NaH, and the like; in a suitablesolvent such as DMF, and the like; to provide a compound of Formula (I),where R² is CH(OCH₃)C₁₋₆alkyl.

A compound of Formula (I), where R² is oxetanyl, is treated with anAgilent Bond Elut strong cation exchange (SCX) cartridge to provide acompound of Formula (I), where R² is CH(OH)CH₂CH₂OCH₃.

Compounds of Formula (I) may be converted to their corresponding saltsusing methods known to one of ordinary skill in the art. For example, anamine of Formula (I) is treated with trifluoroacetic acid, HCl, orcitric acid in a solvent such as diethyl ether (Et₂O), CH₂C₂, THF, MeOH,chloroform, or isopropanol to provide the corresponding salt form.Alternately, trifluoroacetic acid or formic acid salts are obtained as aresult of reverse phase HPLC purification conditions. Cyrstalline formsof pharmaceutically acceptable salts of compounds of Formula (I) may beobtained in crystalline form by recrystallization from polar solvents(including mixtures of polar solvents and aqueous mixtures of polarsolvents) or from non-polar solvents (including mixtures of non-polarsolvents).

Where the compounds according to this invention have at least one chiralcenter, they may accordingly exist as enantiomers. Where the compoundspossess two or more chiral centers, they may additionally exist asdiastereomers. It is to be understood that all such isomers and mixturesthereof are encompassed within the scope of the present invention.

Compounds prepared according to the schemes described above may beobtained as single forms, such as single enantiomers, by form-specificsynthesis, or by resolution. Compounds prepared according to the schemesabove may alternately be obtained as mixtures of various forms, such asracemic (1:1) or non-racemic (not 1:1) mixtures. Where racemic andnon-racemic mixtures of enantiomers are obtained, single enantiomers maybe isolated using conventional separation methods known to one ofordinary skill in the art, such as chiral chromatography,recrystallization, diastereomeric salt formation, derivatization intodiastereomeric adducts, biotransformation, or enzymatic transformation.Where regioisomeric or diastereomeric mixtures are obtained, asapplicable, single isomers may be separated using conventional methodssuch as chromatography or crystallization.

The following specific examples are provided to further illustrate theinvention and various preferred embodiments.

Examples

In obtaining the compounds described in the examples below and thecorresponding analytical data, the following experimental and analyticalprotocols were followed unless otherwise indicated.

Unless otherwise stated, reaction mixtures were magnetically stirred atroom temperature (rt) under a nitrogen atmosphere. Where solutions were“dried,” they were generally dried over a drying agent such as Na₂SO₄ orMgSO₄. Where mixtures, solutions, and extracts were “concentrated”, theywere typically concentrated on a rotary evaporator under reducedpressure.

Reactions under microwave irradiation conditions were carried out in aBiotage Initiator or CEM (Microwave Reactor) Discover instrument.

For the reactions conducted under continuous flow conditions, “flowedthrough a LTF-VS mixer” refers to the use of a Chemyx Fusion 100 TouchSyringe Pump that is in line via 1/16″ PTFE tubing to a LTF-VS mixer(Little Things Factory GmbH (http://www.ltf-gmbh.com), unless otherwiseindicated.

Normal-phase silica gel chromatography (FCC) was performed on silica gel(SiO₂) using prepacked cartridges.

Preparative reverse-phase high performance liquid chromatography (RPHPLC) was performed on either:

METHOD A. An Agilent HPLC with an Xterra Prep RP18 column (5 μM, 30×100or 50×150 mm) or an XBridge C18 OBD column (5 μM, 30×100 or 50×150 mm),and a mobile phase of 5% ACN in 20 mM NH₄OH was held for 2 min, then agradient of 5-99% ACN over 15 min, then held at 99% ACN for 5 min, witha flow rate of 40 or 80 mL/min. or

METHOD B. A Shimadzu LC-8A Series HPLC with an Inertsil ODS-3 column (3m, 30×100 mm, T=45° C.), mobile phase of 5% ACN in H₂O (both with 0.05%TFA) was held for 1 min, then a gradient of 5-99% ACN over 6 min, thenheld at 99% ACN for 3 min, with a flow rate of 80 mL/min. or

METHOD C. A Shimadzu LC-8A Series HPLC with an XBridge C18 OBD column (5m, 50×100 mm), mobile phase of 5% ACN in H₂O (both with 0.05% TFA) washeld for 1 min, then a gradient of 5-99% ACN over 14 min, then held at99% ACN for 10 min, with a flow rate of 80 mL/min. or

METHOD D. A Gilson HPLC with an XBridge C18 column (5 μm, 100×50 mm),mobile phase of 5-99% ACN in 20 mM NH₄OH over 10 min and then hold at 99ACN for 2 min, at a flow rate of 80 mL/min. or

METHOD E. A Wufeng LC100 equipped with a manual Rheodyne 3725i samplerwith a Gemini-NX C18 column (5 μM, 30×100 mm), and a mobile phase of20-100% ACN:8 mM (NH₄)HCO₃ (9:1) in 10 mM aqueous (NH₄)HCO₃ over 16 min,with a flow rate of 40 mL/min. or

METHOD F. A Wufeng LC100 equipped with a manual Rheodyne 3725i samplerwith a Gemini-NX C18 column (5 μM, 30×100 mm), and a mobile phase of50-100% ACN:8 mM (NH₄)HCO₃ (9:1) in 10 mM aqueous (NH₄)HCO₃ over 8 min,with a flow rate of 30 mL/min. or

METHOD G. A Wufeng LC100 equipped with a manual Rheodyne 3725i samplerwith a Gemini-NX C18 column (5 μM, 30×100 mm), and a mobile phase of30-100% ACN:8 mM (NH₄)HCO₃ (9:1) in 10 mM aqueous (NH₄)HCO₃ over 5 min,with a flow rate of 30 mL/min. or

METHOD H. An HPLC equipped with an XBridge C18 OBD column (5 μM, 30×100or 50×150 mm), and a mobile phase of 46-64% ACN:8 mM (NH₄)HCO₃ (9:1) in10 mM aqueous (NH₄)HCO₃.

Preparative supercritical fluid high performance liquid chromatography(SFC) was performed either on a Jasco preparative SFC system, an APS1010 system from Berger instruments, or a SFC-PICLAB-PREP 200 (PICSOLUTION, Avignon, France). The separations were conducted at 100 to 150bar with a flow rate ranging from 40 to 60 mL/min. The column was heatedto 35 to 40° C.

Mass spectra (MS) were obtained on an Agilent series 1100 MSD usingelectrospray ionization (ESI) in positive mode unless otherwiseindicated. Calculated (calcd.) mass corresponds to the exact mass.

Nuclear magnetic resonance (NMR) spectra were obtained on Bruker modelDRX spectrometers. Definitions for multiplicity are as follows:s=singlet, d=doublet, t=triplet, q=quartet, m=multiplet, br=broad. Itwill be understood that for compounds comprising an exchangeable proton,said proton may or may not be visible on an NMR spectrum depending onthe choice of solvent used for running the NMR spectrum and theconcentration of the compound in the solution.

Chemical names were generated using ChemDraw Ultra 17.1 (CambridgeSoftCorp., Cambridge, Mass.) or OEMetaChem V1.4.0.4 (Open Eye).

Compounds designated as R* or S* are enantiopure compounds where theabsolute configuration was not determined.

Intermediate 1: 6-Bromo-3-fluoro-1H-pyrazolo[4,3-b]pyridine

To a solution of 6-bromo-1H-pyrazolo[4,3-b]pyridine (2.5 g, 12.6 mmol)in acetonitrile (62.5 mL) was addedN-fluoro-N-(chloromethyl)triethylenediamine bis(tetrafluoroborate) (6.7g, 18.9 mmol) and the reaction mixture was stirred at 90° C. for 22 h.The reaction mixture was poured into water (120 mL) and was diluted withethyl acetate (EA or EtOAc) (80 mL). The layers were separated, and theaqueous layer was extracted with EtOAc (2×60 mL). The combined organiclayers were dried over MgSO₄, filtered and evaporated. Purification(METHOD E) afforded the title compound (641 mg, 2.97 mmol, 23%) as abrown powder. MS (ESI): mass calcd. for C₆H₃BrFN₃; 214.9 m/z found,216.0 [M+H]⁺.

Intermediate 2: 6-(4-Fluoro-3-methylphenyl)-1H-pyrazolo[4,3-b]pyridine

6-Bromo-1H-pyrazolo[4,3-B]pyridine (1 g, 5.05 mmol),4-fluoro-3-methylphenylboronic acid (1.17 g, 7.58 mmol), Cs₂CO₃ (3.29 g,10.1 mmol), PdCl₂(dppf).DCM (258.66 mg, 0.353 mmol), and 1,4-dioxane(46.6 mL), were combined and heated, with stirring, to 70° C. After twohours the reaction was removed from the heat and allowed to cool to rt.It was then loaded on to a column for purification (FCC, SiO₂, 0-70%EtOAc in hexanes) to afford the title compound (210 mg, 18.3%). MS(ESI): mass calcd for C₁₃H₁₀FN₃, 227.1; m/z found, 228.1 [M+H]⁺.

Intermediate 3:6-(3-(Difluoromethyl)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridine

A mixture of 6-bromo-1H-pyrazolo[4,3-b]pyridine (1.40 g, 7.07 mmol),2-[3-(difluoromethyl)-4-fluoro-phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(2.31 g, 8.49 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.673 g,0.92 mmol) and Na₂CO₃ (2.25 g, 21.2 mmol) in degassed acetonitrile (24.4mL) and water (3.76 mL) was stirred at 120° C. for 4 h under microwaveirradiation. The reaction mixture was poured into water (30 mL) and themixture was extracted with EtOAc (3×30 mL). The combined organic layerswere dried over Na₂SO₄, filtered and evaporated. Purification (FCC,SiO₂, 10 to 50% n-heptane/EtOAc) afforded a solid that was trituratedwith Et₂O (4 mL) to afford the title compound (1.41 g, 5.36 mmol, 76%)as an off-white powder. MS (ESI): mass calcd. for C₁₃HF₃N₃, 263.1; m/zfound, 264.2 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 13.48 (br s, 1H), 8.84(d, J=2.0 Hz, 1H), 8.41-8.30 (m, 1H), 8.30-8.20 (m, 1H), 8.13-7.99 (m,2H), 7.60-7.49 (m, 1H), 7.27 (t, J=54.1 Hz, 1H).

Intermediate 4:6-(3-(Difluoromethoxy)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridine

The title compound was prepared in a manner analogous to Intermediate 3using2-(3-(difluoromethoxy)-4-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolaneinstead of2-[3-(difluoromethyl)-4-fluoro-phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.MS (ESI): mass calcd. for C₁₃H₈F₃N₃O, 279.0; m/z found, 280.2 [M+H]⁺.

Intermediate 5:6-(4-Chloro-3-(difluoromethoxy)phenyl)-1H-pyrazolo[4,3-b]pyridine

The title compound was prepared in a manner analogous to Intermediate 3using2-(3-(difluoromethoxy)-4-chlorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolaneinstead of2-[3-(difluoromethyl)-4-fluoro-phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.MS (ESI): mass calcd. for C₁₃H₈ClF₂N₃O, 295.0; m/z found, 296.0 [M+H]⁺.

Intermediate 6:6-(3-(1,1-Difluoroethyl)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridine

The title compound was prepared in a manner analogous to Intermediate 3using2-(3-(1,1-difluoroethyl)-4-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolaneinstead of2-[3-(difluoromethyl)-4-fluoro-phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.MS (ESI): mass calcd. for C₁₄H₁₀F₃N₃, 277.1; m/z found, 278.1 [M+H]⁺.

Intermediate 7:6-(3-(1,1-Difluoroethyl)phenyl)-1H-pyrazolo[4,3-b]pyridine

The title compound was prepared in a manner analogous to Intermediate 3using2-(3-(1,1-difluoroethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolaneinstead of2-[3-(difluoromethyl)-4-fluoro-phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.MS (ESI): mass calcd. for C₁₄H₁₁F₂N₃, 259.1; m/z found, 260.1 [M+H]⁺.

Intermediate 8: 6-(3-(Trifluoromethyl)phenyl)-1H-pyrazolo[4,3-b]pyridine

A suspension of 6-bromo-1H-pyrazolo[4,3-B]pyridine (5.0 g, 25.25 mmol),3-trifluoromethylphenylboronic acid (5.755 g, 30.3 mmol), Pd(PPh₃)₄(1.459 g, 1.262 mmol) and Na₂CO₃ (2 M in H₂O, 32.468 mL, 64.935 mmol) in1,4-dioxane (96.9 mL) was stirred at 120° C. for 48 h. The mixture wascooled to rt, diluted with EtOAc, and washed with H₂O (×2). The organiclayer was dried over Na₂SO₄ and concentrated under reduced pressure.Purification (FCC, SiO₂, 0-50% EtOAc in heptane), followed bytrituration with Et₂O, afforded the title compound (2.1 g, 32%). MS(ESI): mass calcd. for C₁₃HF₃N₃, 263.1; m/z found, 264.1 [M+H]⁺.

Intermediate 9: 6-(4-Fluorophenyl)-1H-pyrazolo[4,3-b]pyridine

The title compound was prepared in a manner analogous to Intermediate 2using 4-fluorophenylboronic acid instead of4-fluoro-3-methylphenylboronic acid. MS (ESI): mass calcd. forC₁₃H₈F₃N₃, 213.1; m/z found, 214.0 [M+H]⁺.

Intermediate 10:6-(3-(Difluoromethyl)-4-fluorophenyl)-3-methyl-1H-pyrazolo[4,3-b]pyridine

The title compound was prepared in a manner analogous to Intermediate 3,using 6-bromo-3-methyl-1H-pyrazolo[4,3-b]pyridine instead of6-bromo-1H-pyrazolo[4,3-b]pyridine. MS (ESI): mass calcd. forC₁₄H₁₀F₃N₃, 277.1; m/z found, 278.1 [M+H]⁺.

Intermediate 11: 1-(6-Bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)butan-2-one

Under an atmosphere of nitrogen was added6-bromo-1H-pyrazolo[4,3-B]pyridine (500 mg, 2.53 mmol) to a suspensionof NaH (60% dispersion in mineral oil, 141.39 mg, 3.54 mmol) in DMF(21.7 mL) at rt. After 10 min, 1-bromo-2-butanone (0.373 mL, 3.54 mmol)was added, and the reaction mixture was left to stir at rt overnight.The reaction was quenched with a small amount of H₂O, then adsorbed ontosilica gel and purified (FCC, SiO₂, 0-100% EtOAc in hexanes) to affordthe title compound (265 mg, 39%). MS (ESI): mass calcd. for C₁₀H₁₀BrN₃O,267.0; m/z found, 268.0 [M+H]⁺.

Intermediate 12: 1-(6-Bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)propan-2-one

The title compound was prepared in a manner analogous to Intermediate 11using chloroacetone instead of 1-bromo-2-butanone. MS (ESI): mass calcd.for C₉HBrN₃O, 253.0; m/z found, 254.0 [M+H]⁺.

Intermediate 13:1-(6-Bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)-3-methylbutan-2-one

The title compound was prepared in a manner analogous to Intermediate 11using 1-bromo-3-methyl-2-butanone instead of 1-bromo-2-butanone. MS(ESI): mass calcd. for C₁₁H₁₂BrN₃O, 282.1; m/z found 283 [M+H]⁺.

Intermediate 14:2-(6-Bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)-1-cyclopropylethan-1-one

The title compound was prepared in a manner analogous to Intermediate 11using 2-bromo-1-cyclopropylethanone instead of 1-bromo-2-butanone. MS(ESI): mass calcd. for C₁₁H₁₀BrN₃O, 280.1; m/z found 282 [M+H]⁺.

Intermediate 15:1-(6-Bromo-3-fluoro-1H-pyrazolo[4,3-b]pyridin-1-yl)butan-2-one

The title compound was prepared in a manner analogous to Intermediate 11using 6-bromo-3-fluoro-1H-pyrazolo[4,3-b]pyridine (Intermediate 1)instead of 6-bromo-1H-pyrazolo[4,3-b]pyridine. MS (ESI): mass calcd. forC₁₀H₉BrFN₃O, 284.9; m/z found, 286.1 [M+H]⁺.

Intermediate 16:6-Bromo-1-((ethylsulfinyl)methyl)-1H-pyrazolo[4,3-b]pyridine

Step A. 6-Bromo-1-(ethylsulfanylmethyl)pyrazolo[4,3-b]pyridine

A mixture of 6-bromo-1H-pyrazolo[4,3-b]pyridine (600 mg, 3.03 mmol),(chloromethyl)(ethyl)sulfane (369 mg, 3.34 mmol) and Cs₂CO₃ (1.48 g,4.54 mmol) in dry DMF (12 mL) was stirred at room temperature for 20 h.The reaction mixture was poured into water (15 mL) and extracted withEtOAc (3×10 mL). The combined organic layers were dried over Na₂SO₄,filtered and evaporated. Purification (FCC, SiO₂, 0 to 10%hexanes/EtOAc) afforded the title compound (431 mg, 1.584 mmol, 52%) asa pale yellow oil. MS (ESI): mass calcd. for C₉H₁₀BrN₃S, 270.9; m/zfound, 272.0 [M+H]⁺. The reaction also provided6-bromo-2-(ethylsulfanylmethyl)pyrazolo[4,3-b]pyridine (240 mg, 0.882mmol, 29%) as a pale yellow powder. MS (ESI): mass calcd. forC₉H₁₀BrN₃S, 270.9; m/z found, 272.0 [M+H]⁺.

Step B. 6-Bromo-1-(ethylsulfinylmethyl)pyrazolo[4,3-b]pyridine

To a solution of 6-bromo-1-(ethylsulfanylmethyl)pyrazolo[4,3-b]pyridine(421 mg, 1.55 mmol) from Step A in DCM (12.9 mL) was added3-chloroperbenzoic acid (248 mg, 1.11 mmol) at 0° C. The reactionmixture was stirred at 0° C. for 1 h, then at room temperature for 46 h.The reaction mixture was diluted with DCM (12 mL) and washed with 10%Na₂CO₃ (1×15 mL). The aqueous layer was extracted with DCM (2×15 mL) andthe combined organic layers were dried over Na₂SO₄, filtered andevaporated. Purification (FCC, SiO₂, 0 to 5% MeOH in DCM) afforded thetitle compound (290 mg, 1.01 mmol, 91%) as a white powder. MS (ESI):mass calcd. for C₉HioBrN₃OS, 286.9; m/z found, 288.0 [M+H]⁺.

Intermediate 17: 2-Bromo-1-cyclobutylethan-1-one

To cyclobutyl methyl ketone (1.0 g, 10.189 mmol) stirring in MeOH (10mL) at 0° C. was added bromine (1.6 g, 10.012 mmol). The reactionmixture was allowed to stir and slowly warm to rt as the ice bathmelted. After 2 hours, water was added to the reaction mixture and itwas stirred for an additional 30 min. Water (50 mL) was added, and theaqueous layer was extracted with ether (2×50 mL). The organic layer wasdried, filtered, and concentrated under reduced pressure to afford thetitle compound (376 mg, 21%). ¹H NMR (300 MHz, CDCl₃) δ 3.89 (s, 2H),3.70-3.53 (m, 1H), 2.37-2.16 (m, 4H), 2.12-1.97 (m, 1H), 1.95-1.80 (m,1H).

Intermediate 18: (R)-5-(Chloromethyl)-3-methyloxazolidin-2-one

To (R)-5-(hydroxymethyl)-3-methyloxazolidin-2-one (518.2 mg, 3.952 mmol)stirring in DCE (20 mL) in a round bottom flask at rt was added SOCl₂(1.5 mL, 20.677 mmol) followed by pyridine (1.6 mL, 19.863 mmol). Thereaction was connected to a reflux apparatus and stirred at 90° C. for 1h. The reaction mixture was then cooled to rt, then cooled to 0° C. andquenched by the dropwise addition of a saturated aqueous solution ofNaHCO₃ until pH 7 was reached. The layers were separated and the organiclayer was washed with saturated aqueous solutions of NaHCO₃ (×3), NH₄C₁(×3), then CuSO₄ (×2). The organic layer was then dried (Na₂SO₄) andconcentrated under reduced pressure to afford the title compound as ayellow oil (172.2 mg, 29%). ¹H NMR (500 MHz, CDCl₃) δ 4.70 (dddd, J=8.7,7.0, 5.7, 4.1 Hz, 1H), 3.78-3.59 (m, 3H), 3.46 (dd, J=9.0, 5.7 Hz, 1H),2.90 (s, 3H).

Intermediate 19: (S)-5-(Chloromethyl)-3-methyloxazolidin-2-one

The title compound was prepared in a manner analogous to Intermediate 18using (S)-5-(hydroxymethyl)-3-methyloxazolidin-2-one instead of(R)-5-(hydroxymethyl)-3-methyloxazolidin-2-one. ¹H NMR (500 MHz, CDCl₃)δ 4.70 (dddd, J=8.7, 7.0, 5.7, 4.1 Hz, 1H), 3.78-3.59 (m, 3H), 3.46 (dd,J=9.0, 5.7 Hz, 1H), 2.90 (s, 3H).

Intermediate 20: (RS)-4-(Chloromethyl)-3-methyloxazolidin-2-one

The title compound was prepared in a manner analogous to Intermediate 18using (RS)-4-(hydroxymethyl)-3-methyl-1,3-oxazolidin-2-one instead of(R)-5-(hydroxymethyl)-3-methyloxazolidin-2-one. ¹H NMR (500 MHz, CDCl₃)δ 4.48-4.33 (m, 1H), 4.20 (dd, J=9.1, 5.4 Hz, 1H), 4.05-3.89 (m, 1H),3.70-3.56 (m, 2H), 2.91 (s, 3H).

Intermediate 21: 2-Bromo-1-(pyridin-2-yl)ethan-1-one

To a solution of 2-acetylpyridine (500 mg, 4.13 mmol) in acetic acid(AcOH) (6.25 mL, 109 mmol) was added pyridinium tribromide (1.32 g, 4.13mmol) and the reaction mixture was stirred at 50° C. for 17 h. Theprecipitate was collected and was washed with Et₂O (4×5 mL) to give thetitle compound (941 mg, 3.35 mmol, 81%) as an off-white powder. MS(ESI): mass calcd. for C₇H₆BrNO; 198.9 m/z found, 200.1 [M+H]⁺.

Intermediate 22: 2-Bromo-1-(pyridin-4-yl)ethan-1-one

The title compound was prepared in a manner analogous to Intermediate 21using 1-(pyridin-4-yl)ethan-1-one instead of 2-acetylpyridine. MS (ESI):mass calcd. for C₇H₆BrNO; 198.9 m/z found, 200.1 [M+H]⁺.

Intermediate 23: 2-Bromo-1-(3,5-difluoropyridin-2-yl)ethan-1-one

To a solution of phenyltrimethylammonium tribromide (420 mg, 1.12 mmol)in THE (3.5 mL) was added a solution of1-(3,5-difluoropyridin-2-yl)ethanone (160 mg, 1.02 mmol) in THE (1.5 mL)and the reaction mixture was stirred at 60° C. for 1 h. The mixture wasfiltered and the solids washed with THE (5×5 mL). The combined filtrateswere concentrated. Purification (FCC, SiO₂, 0 to 100% n-heptane/DCM)afforded the title compound (142 mg, 0.651 mmol, 64%) as a pale yellowoil. No mass found in MS.

Intermediate 24: 2-Bromo-1-(3-fluoropyridin-2-yl)ethan-1-one

The title compound was prepared in a manner analogous to Intermediate 23using 1-(3-fluoropyridin-2-yl)ethan-1-one instead of1-(3,5-difluoropyridin-2-yl)ethanone. Material used without furtherpurification. No mass found in MS.

Intermediate 25: 2-Bromo-1-(pyrazin-2-yl)ethan-1-one

The title compound was prepared in a manner analogous to Intermediate 23using 1-(pyrazin-2-yl)ethan-1-one instead of1-(3,5-difluoropyridin-2-yl)ethanone. Material used without furtherpurification. No mass found in MS.

Intermediate 26: 2-Bromo-1-(pyrimidin-2-yl)ethan-1-one

The title compound was prepared in a manner analogous to Intermediate 23using 1-(pyrimidin-2-yl)ethan-1-one instead of1-(3,5-difluoropyridin-2-yl)ethanone. Material used without furtherpurification. No mass found in MS.

Intermediate 27: 2-Bromo-1-(pyridin-3-yl)ethan-1-one

To a solution of 3-acetylpyridine (500 mg, 4.128 mmol) and HBr (33 wt %in acetic acid, 1.25 mL, 7.238 mmol) in acetic acid (1.25 mL) was addedpyridinium tribromide (1.45 g, 4.534 mmol) and the reaction mixture wasstirred at rt for 30 min. Diethyl ether (8 mL) was added to thereaction, and the mixture was cooled to 0° C. The precipitate wascollected and washed with diethyl ether (5×5 mL) to afford the titlecompound as an off-white powder (1.921 g, 165%). MS (ESI): mass calcd.for C₇H₆BrNO; 198.9 m/z found, 200.1 [M+H]⁺.

Intermediate 28: 2-Bromo-1-(5-fluoropyridin-2-yl)ethan-1-one

The title compound was prepared in a manner analogous to Intermediate 23using 1-(5-fluoropyridin-2-yl)ethanone instead of1-(3,5-difluoropyridin-2-yl)ethanone. No mass found in MS.

Intermediate 29:2-(3-(Difluoromethyl)-4-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

A solution of 4-bromo-2-(difluoromethyl)-1-fluorobenzene (20 g, 88.9mmol), bis(pinacolato)diboron (24.8 g, 97.8 mmol), potassium acetate(26.2 g, 267 mmol), and[1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (3.12 g,4.44 mmol) in 1,4-dioxane (400 mL) was purged with N₂, and the reactionmixture was stirred at 90° C. overnight. Upon completion, the reactionmixture was cooled to room temperature, filtered through Celite®, andrinsed with EtOAc. The filtrate was washed with water and brine. Thecombined organics were dried with Na₂SO₄, filtered and concentrated toyield a clear oil (22.1 g, 81.0 mmol, 91%), which solidified uponstanding. ¹H NMR (400 MHz, Chloroform-d) δ 8.12-8.00 (m, 1H), 7.96-7.85(m, 1H), 7.17-7.06 (m, 1H), 6.88 (t, J=54.9 Hz, 1H), 1.35 (s, 12H). MS(ESI): mass calcd. for C₁₃H₁₆BF₃O₂, 272.1; m/z found, 273.0 [M+H]⁺.

Intermediate 30:2-(3-(1,1-Difluoroethyl)-4-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

Step A: 4-Bromo-2-(1,1-difluoroethyl)-1-fluorobenzene

In a round bottom flask, a mixture of1-(5-bromo-2-fluorophenyl)-1-ethanone (2.5 g, 11.5 mmol, 1 equiv) andDAST (1.9 mL, 14.4 mmol, 1.25 equiv) was heated at 60° C. for 16 h. Thena sat. aq. solution of NaHCO₃ was slowly added at 0° C. and the mixturewas extracted with DCM. The organic layers were combined, dried overMgSO₄, filtered, and partially concentrated (product is volatile).Purification (FCC, SiO₂, 100% DCM) afforded the title compound (3 g, 7.5mmol, purity 60%, 65%) as a brown oil. ¹H NMR (300 MHz, CDCl₃) δ7.73-7.61 (m, 1H), 7.60-7.48 (m, 1H), 7.02 (t, J=9.4 Hz, 1H), 1.98 (t,J=18.6 Hz, 3H).

Step B:2-(3-(1,1-Difluoroethyl)-4-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

In a round bottom flask, bis(pinacolato)diboron (2.87 g, 11.3 mmol, 1.5equiv), potassium acetate (2.22 g, 22.6 mmol, 3 equiv), and[1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (615 mg,0.75 mmol, 0.1 equiv) were added to a solution of4-bromo-2-(1,1-difluoroethyl)-1-fluorobenzene (3 g, 7.5 mmol, 1 equiv)in dry 1,4-dioxane (40 mL). The reaction mixture was purged withnitrogen and stirred at 90° C. for 16 h. Then, a sat. aq. solution ofNaHCO₃ was added and the mixture was extracted with EtOAc. The combinedorganics were dried with MgSO₄, filtered and concentrated to afford thetitle compound as a brown oil (2.15 g, 7.53 mmol), which was used in thenext step without further purification. MS (ESI): mass calcd. forC₁₄H₁₈BF₃O₂, 286.1; m/z found, 287.1 [M+H]⁺.

Intermediate 31:2-(3-(Difluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

The title compound was prepared in a manner analogous to Intermediate 29using 1-bromo-3-(difluoromethyl)benzene instead of4-bromo-2-(difluoromethyl)-1-fluorobenzene. No mass observed.

Intermediate 32:2-(3-(1,1-Difluoroethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

The title compound was prepared in a manner analogous to Intermediate 29using 1-bromo-3-(1,1-difluoroethyl)benzene instead of4-bromo-2-(difluoromethyl)-1-fluorobenzene. No mass observed.

Intermediate 33:2-(3-(Difluoromethoxy)-4-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

The title compound was prepared in a manner analogous to Intermediate 29using 4-bromo-2-(difluoromethoxy)-1-fluorobenzene instead of4-bromo-2-(difluoromethyl)-1-fluorobenzene. MS (ESI): mass calcd. forC₁₃H₁₆BF₃O₃, 288.1; m/z found, 289.0 [M+H]⁺.

Intermediate 34:2-(4-Chloro-3-(difluoromethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

The title compound was prepared in a manner analogous to Intermediate 29using 4-bromo-1-chloro-2-(difluoromethoxy)benzene instead of4-bromo-2-(difluoromethyl)-1-fluorobenzene. 1H NMR (500 MHz, CDCl₃) δ7.62-7.56 (m, 2H), 7.44 (d, J=7.9 Hz, 1H), 6.56 (t, J=73.6 Hz, 1H), 1.34(s, 12H).

Example 1:1-[6-(3,5-Difluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]butan-2-one

1-(6-Bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)butan-2-one (Intermediate 11,30 mg, 0.112 mmol), 3,5-difluorophenylboronic acid (21.2 mg, 0.134mmol), Cs₂CO₃ (109 mg, 0.336 mmol), Pd(dppf)C₁₂.DCM (8.2 mg, 0.0112mmol), and 1,4-dioxane (1 mL) were combined and heated, with stirring,to 90° C. overnight. After cooling to rt, the crude material was loadeddirectly onto a column and purified (FCC, SiO₂, 0-100% EtOAc in hexanes)to afford the title compound (37.4 mg, 111%). MS (ESI): mass calcd. forC₁₆H₁₃F₂N₃O, 301.1; m/z found, 302.0 [M+H]⁺.

Example 2:3-Methyl-1-[6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]butan-2-one

The title compound was prepared in a manner analogous to Example 1 using1-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)-3-methylbutan-2-one(Intermediate 13) instead of1-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)butan-2-one (Intermediate 11),and 3-trifluoromethyl-phenylboronic acid instead of3,5-difluorophenylboronic acid. MS (ESI): mass calcd. for C₁₈H₁₆F₃N₃O,347.1; m/z found, 348.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO) δ 8.94 (d, J=2.0Hz, 1H), 8.47-8.43 (m, 1H), 8.40-8.38 (m, 1H), 8.16-8.10 (m, 2H),7.85-7.75 (m, 2H), 5.67 (s, 2H), 2.89-2.77 (m, 1H), 1.13 (m, 6H).

Example 3:(RS)-3-Methyl-1-[6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]butan-2-ol

To3-methyl-1-[6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]butan-2-one(Example 2, 50 mg, 0.144 mmol) stirring in THE (1.885 mL) and MeOH(1.885 mL) at 0° C. was added NaBH₄ (10.89 mg, 0.288 mmol). The reactionmixture was stirred at this temperature for 30 min, then warmed to rt.The reaction mixture was concentrated under reduced pressure and takenup in EtOAc. The organic layer was washed with water, dried, andconcentrated under reduced pressure to afford the title compound (34.6mg, 69%). MS (ESI): mass calcd. for C₁₈H₁₈F₃N₃O, 349.1; m/z found, 350.0[M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 8.89 (d, J=1.9 Hz, 1H), 8.52-8.50(m, 1H), 8.34-8.33 (m, 1H), 8.17-8.13 (m, 2H), 7.84-7.77 (m, 2H), 4.79(d, J=6.0 Hz, 1H), 4.50-4.46 (m, 2H), 3.69 (p, J=5.8 Hz, 1H), 1.68-1.59(m, 1H), 0.97 (d, J=6.9 Hz, 3H), 0.94 (d, J=6.7 Hz, 3H).

Example 4:1-[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]butan-2-one

The title compound was prepared in a manner analogous to Intermediate16, Step A, using6-(3-(difluoromethyl)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 3) instead of 6-bromo-1H-pyrazolo[4,3-B]pyridine, and1-bromo-2-butanone instead of (chloromethyl)(ethyl)sulfane. MS (ESI):mass calcd. for C₁₇H₁₄F₃N₃O, 333.1; m/z found, 334.1 [M+H]⁺. ¹H NMR (500MHz, DMSO-d₆) δ 8.88 (d, J=2.0 Hz, 1H), 8.44-8.41 (m, 1H), 8.38-8.36 (m,1H), 8.08-8.01 (m, 2H), 7.61-7.53 (m, 1H), 7.29 (t, J=54.2 Hz, 1H), 5.54(s, 2H), 2.57 (q, J=7.3 Hz, 2H), 0.98 (t, J=7.3 Hz, 3H).

Example 5:(RS)-1-[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]butan-2-ol

To a solution of1-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]butan-2-one(Example 4.45 mg, 0.135 mmol) in methanol (1.5 mL) was added sodiumborohydride (13 mg, 0.344 mmol) at 0° C. The reaction mixture was warmedto room temperature and stirred for 1 h. Water (5 mL) was added and themixture was extracted with EtOAc (2×5 mL). The combined organics weredried over Na₂SO₄, filtered and evaporated. Purification (FCC, SiO₂, 0to 5% MeOH in DCM) afforded the title compound (35 mg, 0.104 mmol, 77%)as a white powder. MS (ESI): mass calcd. for C₁₇H₁₆F₃N₃O, 335.1; m/zfound, 336.1 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 8.84 (d, J=1.9 Hz, 1H),8.51-8.40 (m, 1H), 8.38-8.26 (m, 1H), 8.16-8.00 (m, 2H), 7.64-7.52 (m,1H), 7.30 (t, J=54.1 Hz, 1H), 4.85 (d, J=5.6 Hz, 1H), 4.44 (d, J=5.7 Hz,2H), 3.92-3.76 (m, 1H), 1.57-1.26 (m, 2H), 0.93 (t, J=7.4 Hz, 3H).

Example 6:(E/Z)-3-Methyl-1-[6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]butan-2-oneoxime

To3-methyl-1-[6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]butan-2-one(Example 2, 20 mg, 0.0576 mmol) stirring in MeOH (2 mL) was added anaqueous solution of hydroxylamine hydrochloride (8.0 mg, 0.115 mmol) andNaHCO₃ (9.8 mg, 0.115 mmol) in 0.5 mL H₂O. The reaction was stirred atrt overnight. The reaction was then diluted with H₂O and extracted withEtOAc. The organic layer was dried and concentrated under reducedpressure to afford the title compound (20.1 mg, 96%). MS (ESI): masscalcd. for CH₁₇F₃N₄O, 362.1; m/z found, 363.0 [M+H]⁺.

Example 7:1-[6-(4-Fluoro-3-methyl-phenyl)pyrazolo[4,3-b]pyridin-1-yl]-3-methyl-butan-2-one

The title compound was prepared in a manner analogous to Example 1 using1-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)-3-methylbutan-2-one(Intermediate 13) instead of1-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)butan-2-one (Intermediate 11),and 4-fluoro-3-methylphenylboronic acid instead of3,5-difluorophenylboronic acid. MS (ESI): mass calcd. for C₁₈H₁₈FN₃O,311.1; m/z found, 312.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO) δ 8.85 (d, J=1.9Hz, 1H), 8.35-8.33 (m, 1H), 8.32-8.30 (m, 1H), 7.76-7.71 (m, 1H),7.67-7.62 (m, 1H), 7.35-7.27 (m, 1H), 5.65 (s, 2H), 2.89-2.77 (m, 1H),2.36-2.32 (m, 3H), 1.12 (d, J=6.9 Hz, 6H).

Example 8:(RS)-1-[6-(4-Fluoro-3-methyl-phenyl)pyrazolo[4,3-b]pyridin-1-yl]-3-methyl-butan-2-ol

The title compound was prepared in a manner analogous to Example 3 using1-[6-(4-fluoro-3-methyl-phenyl)pyrazolo[4,3-b]pyridin-1-yl]-3-methyl-butan-2-one(Example 7) instead of3-methyl-1-[6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]butan-2-one.MS (ESI): mass calcd. for C₁₈H₂₀FN₃O, 313.2; m/z found, 314.1 [M+H]⁺. ¹HNMR (500 MHz, DMSO) δ 8.80 (d, J=1.9 Hz, 1H), 8.36-8.34 (m, 1H),8.30-8.28 (m, 1H), 7.78-7.75 (m, 1H), 7.69-7.64 (m, 1H), 7.34-7.29 (m,1H), 4.79 (d, J=5.9 Hz, 1H), 4.48-4.42 (m, 2H), 3.71-3.65 (m, 1H),2.36-2.33 (m, 3H), 1.68-1.58 (m, 1H), 0.97 (d, J=6.8 Hz, 3H), 0.94 (d,J=6.8 Hz, 3H).

Example 9:1-Cyclopropyl-2-[6-(3,4,5-trifluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]ethanone

The title compound was prepared in a manner analogous to Example 1 using2-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)-1-cyclopropylethan-1-one(Intermediate 14) instead of1-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)butan-2-one (Intermediate 11),and 3,4,5-trifluorophenylboronic acid instead of3,5-difluorophenylboronic acid. MS (ESI): mass calcd. for C₁₇H₁₂F₃N₃O,331.1; m/z found, 332.0 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 8.94 (d,J=2.0 Hz, 1H), 8.54-8.51 (m, 1H), 8.39-8.37 (m, 1H), 7.92-7.85 (m, 2H),5.69 (s, 2H), 2.16-2.09 (m, 1H), 1.04-0.92 (m, 4H).

Example 10:(R/S)-1-Cyclopropyl-2-[6-(3,4,5-trifluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]ethanol

The title compound was prepared in a manner analogous to Example 3 using1-cyclopropyl-2-[6-(3,4,5-trifluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]ethanone(Example 9) instead of3-methyl-1-[6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]butan-2-one.MS (ESI): mass calcd. for C₁₇H₁₄F₃N₃O, 333.1; m/z found, 334.0 [M+H]⁺.

Example 11:(R/S)-1-(2-Cyclopropyl-2-methoxy-ethyl)-6-(3,4,5-trifluorophenyl)pyrazolo[4,3-b]pyridine

To(RS)-1-cyclopropyl-2-[6-(3,4,5-trifluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]ethanol(Example 10, 15 mg, 0.045 mmol) stirring in DMF (0.86 mL) at rt wasadded NaH (60% dispersion in mineral oil, 3.6 mg, 0.09 mmol). Themixture was stirred at rt for 10 min, then iodomethane (0.00336 mL) wasadded, and the reaction mixture was stirred at rt for 3 h. The reactionwas quenched with H₂O, then evaporated under reduced pressure. Theresidue was dissolved in MeOH and purified by prep HPLC (METHOD A) toafford the title compound (2.4 mg, 15%). MS (ESI): mass calcd. forC₁₈H₁₆F₃N₃O, 347.1; m/z found, 347.9 [M+H]⁺. ¹H NMR (400 MHz, DMSO) δ8.90 (d, J=2.0 Hz, 1H), 8.58-8.53 (m, 1H), 8.36-8.32 (m, 1H), 7.96-7.87(m, 2H), 4.70-4.55 (m, 2H), 3.19 (s, 3H), 3.10-3.03 (m, 1H), 0.86-0.74(m, 1H), 0.57-0.46 (m, 1H), 0.43-0.34 (m, 1H), 0.27-0.18 (m, 1H),−0.08-0.16 (m, 1H).

Example 12:(RS)-6-[3-(Difluoromethoxy)-4-fluoro-phenyl]-1-(ethylsulfinylmethyl)pyrazolo[4,3-b]pyridine

The title compound was prepared in a manner analogous to Intermediate 3,using 6-bromo-1-((ethylsulfinyl)methyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 16) instead of6-bromo-3-methyl-1H-pyrazolo[4,3-b]pyridine, and2-(3-(difluoromethoxy)-4-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolaneinstead of2-(3-(difluoromethyl)-4-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.MS (ESI): mass calcd. for C₁₆H₁₄F₃N₃O₂S, 369.1; m/z found, 370.1 [M+H]⁺.¹H NMR (500 MHz, DMSO-d₆) δ 8.92 (d, J=2.0 Hz, 1H), 8.58 (dd, J=2.0, 1.0Hz, 1H), 8.50 (d, J=0.9 Hz, 1H), 7.82 (dd, J=7.5, 2.3 Hz, 1H), 7.78-7.72(m, 1H), 7.62 (dd, J=10.5, 8.6 Hz, 1H), 7.38 (t, J=73.2 Hz, 1H), 5.92(d, J=13.7 Hz, 1H), 5.76 (d, J=13.7 Hz, 1H), 2.98-2.89 (m, 1H),2.84-2.76 (m, 1H), 1.25 (t, J=7.5 Hz, 3H).

Example 13:6-[3-(Difluoromethoxy)-4-fluoro-phenyl]-1-(ethylsulfonylmethyl)pyrazolo[4,3-b]pyridine

Step A:6-(3-(Difluoromethoxv)-4-fluorophenyl)-1-((ethylsulfonyl)methyl)-1H-pyrazolo[4,3-b]pyridine4-oxide

m-CPBA (6.8 mg, 0.03 mmol) was added to a solution of(RS)-6-[3-(difluoromethoxy)-4-fluoro-phenyl]-1-(ethylsulfinylmethyl)pyrazolo[4,3-b]pyridine(Example 12, 8.63 mg, 0.02 mmol) in DCM (2 mL) at room temperature.After 16 hours, the reaction mixture was quenched with saturated aqueousNaHCO₃ (10 mL). The mixture was extracted with DCM (3×150 mL). Thecombined organic layers were dried (MgSO₄), filtered and concentratedunder vacuum to provide the title compound. MS (ESI): mass calcd. forC₁₆H₁₄F₃N₃O₄S, 401.1; m/z found, 402.1 [M+H]⁺.

Step B:6-[3-(Difluoromethoxv)-4-fluoro-phenyl]-1-(ethylsulfonylmethyl)pyrazolo[4,3-b]pyridine

A mixture of6-(3-(difluoromethoxy)-4-fluorophenyl)-1-((ethylsulfonyl)methyl)-1H-pyrazolo[4,3-b]pyridine4-oxide (9.4 mg, 0.02 mmol) from Step A and Pd/C (10 wt. %, 1.2 mg,0.001 mmol) in EtOH (2.0 mL) and EtOAc (2.0 mL) was stirred at roomtemperature under a nitrogen atmosphere. After 16 hours, the reactionmixture was filtered. The filtrate was purified (HPLC, METHOD D) toprovide the title compound (3.7 mg, 41%). MS (ESI): mass calcd. forC₁₆H₁₄F₃N₃O₃S, 385.1; m/z found, 386.1 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆)δ 8.97 (d, J=2.0 Hz, 1H), 8.69-8.67 (m, 1H), 8.57-8.55 (m, 1H),7.85-7.82 (m, 1H), 7.79-7.75 (m, 1H), 7.63 (dd, J=10.5, 8.6 Hz, 1H),7.39 (t, J=73.1 Hz, 1H), 6.20 (s, 2H), 3.16 (q, J=7.4 Hz, 2H), 1.26 (t,J=7.5 Hz, 3H).

Example 14:2-[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1-(2-pyridyl)ethanone

To a solution of6-[3-(difluoromethyl)-4-fluoro-phenyl]-1H-pyrazolo[4,3-b]pyridine(Intermediate 3, 100 mg, 0.380 mmol) in acetonitrile (2 mL) was addedCs₂CO₃ (371 mg, 1.14 mmol) and the reaction mixture was stirred at roomtemperature for 30 min. To the reaction mixture was added2-bromo-1-(2-pyridyl)ethanone hydrobromide (Intermediate 21, 140 mg,0.498 mmol) and the reaction mixture was stirred at room temperature for22 h. The mixture was then diluted with water (8 mL) and extracted withEtOAc (3×8 mL). The combined organics were dried over Na₂SO₄, filteredand evaporated. Purification (FCC, SiO₂, 0 to 5% DCM/MeOH) afforded asolid that was recrystallized from ethanol (3 mL) to give the titlecompound (44 mg, 0.115 mmol, 30%) as an off-white powder. MS (ESI): masscalcd. for C₂₀H₁₃F₃N₄O, 382.1; m/z found, 383.1 [M+H]⁺. ¹H NMR (500 MHz,DMSO-d₆) δ 8.92 (d, J=1.9 Hz, 1H), 8.88-8.85 (m, 1H), 8.60-8.56 (m, 1H),8.43-8.40 (m, 1H), 8.09 (td, J=7.7, 1.8 Hz, 1H), 8.07-8.03 (m, 2H),8.02-7.97 (m, 1H), 7.81-7.76 (m, 1H), 7.57-7.51 (m, 1H), 7.27 (t, J=54.1Hz, 1H), 6.33 (s, 2H).

Example 15:2-(6-(3-(Difluoromethyl)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)-1-(5-fluoropyridin-2-yl)ethan-1-one

A mixture of6-[3-(difluoromethyl)-4-fluoro-phenyl]-1H-pyrazolo[4,3-b]pyridine(Intermediate 3, 150 mg, 0.57 mmol) and NaHCO₃ (105 mg, 1.25 mmol) inDMF (2.9 mL) was stirred at rt for 30 min. To the reaction mixture wasadded 2-bromo-1-(5-fluoropyridin-2-yl)ethan-1-one (Intermediate 28, 149mg, 0.683 mmol) in DMF (1 mL) and the reaction mixture was stirred at rtfor 3 h. Additional NaHCO₃ (105 mg, 1.25 mmol) and a solution of2-bromo-1-(5-fluoropyridin-2-yl)ethan-1-one (Intermediate 28, 149 mg,0.683 mmol) in DMF (1 mL) was added and the reaction mixture was stirredat rt for 17 h. The reaction was evaporated under reduced pressure, andthe residue was purified (FCC, SiO₂, dichloromethane:methanol (100/0 to98/2), then re-purified by n-hexane/ethyl acetate (4/1 to ½)). Theproduct was re-purified by prep HPLC (METHOD E) and triturated withdiethyl ether (4 mL) to afford the title compound. MS (ESI): mass calcd.for C₂₀H₁₂F₄N₄O, 400.1; m/z found, 401.1 [M+H]⁺. ¹H NMR (500 MHz,DMSO-d₆) δ 8.95-8.90 (m, 1H), 8.90-8.85 (m, 1H), 8.59-8.55 (m, 1H),8.44-8.39 (m, 1H), 8.11 (dd, J=8.8, 4.6 Hz, 1H), 8.08-8.03 (m, 2H), 8.00(td, J=8.7, 2.6 Hz, 1H), 7.58-7.51 (m, 1H), 7.27 (t, J=54.1 Hz, 1H),6.30 (s, 2H).

Example 16:2-(6-(3-(Difluoromethyl)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)-1-(pyridin-3-yl)ethan-1-one

To a solution of6-[3-(difluoromethyl)-4-fluoro-phenyl]-1H-pyrazolo[4,3-b]pyridine(Intermediate 3, 150 mg, 0.57 mmol) and DIPEA (300 μL, 1.722 mmol) inDMF (3.9 mL) was added 2-bromo-1-(pyridin-3-yl)ethan-1-one HBr salt(Intermediate 27, 192 mg, 0.683 mmol) and the reaction mixture wasstirred at rt for 1 h. Over the next 75 h, 6 additional portions ofDIPEA (300 μL, 1.722 mmol) for a total of 2.1 mL (12.06 mmol) and2-bromo-1-(pyridine-3-yl)ethan-1-one HBr salt (192 mg, 0.683 mmol) for atotal of 1.34 g (4.78 mmol) were added. The reaction mixture was pouredinto water (20 mL), then extracted with ethyl acetate (3×20 mL). Thecombined organic layers were dried (Na₂SO₄), filtered, and evaporated.The residue was purified (FCC, SiO₂, n-hexane/ethyl acetate/methanol(2:1:0 to 0:1:0 to 0:20:1) to afford the title compound. MS (ESI): masscalcd. for C₂₀H₁₃F₃N₄O, 382.1; m/z found, 383.1 [M+H]⁺. ¹H NMR (500 MHz,DMSO-d₆) δ 9.33-9.26 (m, 1H), 8.92 (d, J=2.0 Hz, 1H), 8.89 (dd, J=4.9,1.7 Hz, 1H), 8.56-8.51 (m, 1H), 8.46-8.39 (m, 2H), 8.09-7.98 (m, 2H),7.66 (dd, J=7.9, 4.8 Hz, 1H), 7.59-7.50 (m, 1H), 7.27 (t, J=54.1 Hz,1H), 6.34 (s, 2H).

Example 17:(RS)-1-(Oxetan-2-ylmethyl)-6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridine

To a suspension of NaH (60% dispersion in mineral oil, 28.9 mg, 0.723mmol) in DMF (5.4 mL) at rt under an atmosphere of N₂ was added6-(3-(trifluoromethyl)phenyl)-1H-pyrazolo[4,3-b]pyridine (Intermediate8, 136 mg, 0.517 mmol). After 10 minutes, 2-(bromomethyl)oxetane (0.0697mL, 0.723 mmol) was added and the reaction mixture was heated to 75° C.Upon completion the reaction mixture was cooled to rt and water (20 mL)was added. The mixture was extracted using EtOAc (3×30 mL) and thecombined organic layers were dried over MgSO₄, filtered and concentratedunder vacuum. Purification by prep HPLC (METHOD A) afforded the titlecompound and(RS)-4-methoxy-1-[6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]butan-2-ol.MS (ESI): mass calcd. for C₁₇H₁₄F₃N₃O, 333.1; m/z found, 334.2 [M+H]⁺.¹H NMR (400 MHz, CDCl₃) δ 8.82 (d, J=1.9 Hz, 1H), 8.33-8.31 (m, 1H),8.12-8.09 (m, 1H), 7.91-7.88 (m, 1H), 7.86-7.82 (m, 1H), 7.72-7.61 (m,2H), 5.31-5.24 (m, 1H), 4.71-4.67 (m, 2H), 4.61-4.54 (m, 1H), 4.19-4.13(m, 1H), 2.80-2.70 (m, 1H), 2.60-2.50 (m, 1H).

Example 18:(RS)-6-[3-(Difluoromethyl)-4-fluoro-phenyl]-1-(tetrahydrofuran-2-ylmethyl)pyrazolo[4,3-b]pyridine

A mixture of6-[3-(difluoromethyl)-4-fluoro-phenyl]-1H-pyrazolo[4,3-b]pyridine(Intermediate 3, 150 mg, 0.570 mmol), 2-(chloromethyl)oxolane (76 mg,0.63 mmol), Cs₂CO₃ (279 mg, 0.856 mmol) and potassium iodide (19 mg,0.114 mmol) in dry DMF (3 mL) was stirred at 80° C. for 20 h. Thereaction mixture was poured into water (5 mL) and extracted with EtOAc(3×5 mL).

The combined organics were dried over Na₂SO₄, filtered and evaporated.The residue was purified by preparative HPLC (METHOD F) to afford thetitle compound (42 mg, 0.121 mmol, 21%) as a brown oil. MS (ESI): masscalcd. for C₁₈H₁₆F₃N₃O, 347.1; m/z found, 348.1 [M+H]⁺. ¹H NMR (300 MHz,DMSO-d₆) δ 8.85 (d, J=1.9 Hz, 1H), 8.54-8.46 (m, 1H), 8.33 (s, 1H),8.13-7.99 (m, 2H), 7.63-7.52 (m, 1H), 7.30 (t, J=54.1 Hz, 1H), 4.57 (d,J=5.6 Hz, 2H), 4.36-4.24 (m, 1H), 3.73-3.62 (m, 1H), 3.63-3.52 (m, 1H),2.02-1.87 (m, 1H), 1.84-1.59 (m, 3H).

Example 19:(RS)-4-[[6-[3-(Difluoromethoxy)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-1-methyl-pyrrolidin-2-one

A mixture of6-[3-(difluoromethoxy)-4-fluoro-phenyl]-1H-pyrazolo[4,3-b]pyridine(Intermediate 4, 60 mg, 0.215 mmol),4-(chloromethyl)-1-methyl-pyrrolidin-2-one (35 mg, 0.237 mmol) andCs₂CO₃ (420 mg, 1.29 mmol) in dry DMF (1.2 mL) was stirred at roomtemperature for 2 h, then at 60° C. for 11 h. The reaction mixture wasthen cooled, and diluted with water (5 mL), and extracted with EtOAc(2×). The combined organics were dried over Na₂SO₄, filtered andevaporated. Purification (FCC, SiO₂, 5 to 10% DCM/MeOH) afforded thetitle compound (17 mg, 0.044 mmol, 20%) as an off-white powder aftertriturating the solid with diethyl ether. MS (ESI): mass calcd. forC₁₉H₁₇F₃N₄O₂, 390.1; m/z found, 391.1 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆)δ 8.89 (d, J=1.9 Hz, 1H), 8.61-8.54 (m, 1H), 8.39-8.32 (m, 1H), 7.87(dd, J=7.6, 2.3 Hz, 1H), 7.83-7.77 (m, 1H), 7.60 (dd, J=10.5, 8.6 Hz,1H), 7.38 (t, J=73.2 Hz, 1H), 4.57 (d, J=7.4 Hz, 2H), 3.35 (dd, J=9.9,8.0 Hz, 1H), 3.20 (dd, J=9.9, 5.6 Hz, 1H), 3.06-2.96 (m, 1H), 2.68 (s,3H), 2.34 (dd, J=16.7, 8.8 Hz, 1H), 2.14 (dd, J=16.7, 6.6 Hz, 1H).

Example 20:(RS)-5-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]oxazolidin-2-one

To a suspension of sodium hydride (60% in mineral oil, 18 mg, 0.45 mmol)in dry DMF (1 mL) was added a solution of6-[3-(difluoromethyl)-4-fluoro-phenyl]-1H-pyrazolo[4,3-b]pyridine(Intermediate 3, 100 mg, 0.38 mmol) in dry DMF (500 μL) at 0° C. and thereaction was stirred at 0° C. for 30 min. To the reaction mixture wasadded a solution of 5-chloromethyl-2-oxazolidinone (77 mg, 0.568 mmol)in dry DMF (500 μL) and the reaction mixture was stirred at 80° C. for18 h under argon. The reaction mixture was poured into water (10 mL) andextracted with EtOAc (3×5 mL). The combined organics were dried overMgSO₄, filtered and evaporated. Purification (FCC, SiO₂, 0 to 5%CHCl₃/MeOH) afforded the title compound (46 mg, 0.127 mmol, 33%) as awhite powder. MS (ESI): mass calcd. for C₁₇H₁₃F₃N₄O₂, 362.1; m/z found,363.1 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 8.88 (d, J=1.9 Hz, 1H),8.55-8.52 (m, 1H), 8.39 (d, J=0.9 Hz, 1H), 8.12-8.04 (m, 2H), 7.61-7.55(m, 1H), 7.52-7.47 (m, 1H), 7.29 (t, J=54.2 Hz, 1H), 5.09-5.00 (m, 1H),4.84 (dd, J=15.0, 6.4 Hz, 1H), 4.79 (dd, J=15.1, 4.5 Hz, 1H), 3.66-3.60(m, 1H), 3.38-3.33 (m, 1H).

Example 21:(S)-5-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]oxazolidin-2-one

The title compound was prepared by the separation of(RS)-5-[[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]oxazolidin-2-one(Example 20) using chiral SFC (Stationary phase: Chiralpak IA, 5 um250×21 mm, Mobile phase: 20% methanol, 80% CO₂). MS (ESI): mass calcd.for C₁₇H₁₃F₃N₄O₂, 362.1; m/z found, 363.1 [M+H]⁺.

Example 22:(R)-5-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]oxazolidin-2-one

The title compound was prepared by the separation of(RS)-5-[[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]oxazolidin-2-one(Example 20) using chiral SFC (Stationary phase: Chiralpak IA, Sum250×21 mm, Mobile phase: 20% methanol, 80% CO₂). MS (ESI): mass calcd.for C₁₇H₁₃F₃N₄O₂, 362.1; m/z found, 363.1 [M+H]⁺.

Example 23:1-[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]propan-2-one

The title compound was prepared in a manner analogous to Intermediate16, Step A using6-(3-(difluoromethyl)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 3) instead of 6-bromo-1H-pyrazolo[4,3-b]pyridine, andchloropropane-2-one instead of (chloromethyl)(ethyl)sulfane. MS (ESI):mass calcd. for C₁₆H₁₂F₃N₃O, 319.1; m/z found, 320.1 [M+H]⁺. ¹H NMR (500MHz, DMSO-d₆) δ 8.89 (d, J=1.9 Hz, 1H), 8.44-8.43 (m, 1H), 8.37 (d,J=1.0 Hz, 1H), 8.08-8.00 (m, 2H), 7.62-7.53 (m, 1H), 7.30 (t, J=54.1 Hz,1H), 5.55 (s, 2H), 2.21 (s, 3H).

Example 24:1-[6-(4-Fluoro-3-methyl-phenyl)pyrazolo[4,3-b]pyridin-1-yl]propan-2-one

The title compound was prepared in a manner analogous to Intermediate 3,using 1-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)propan-2-one(Intermediate 12) instead of 6-bromo-1H-pyrazolo[4,3-B]pyridine, and4-fluoro-3-methylphenylboronic acid instead of2-[3-(difluoromethyl)-4-fluoro-phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.MS (ESI): mass calcd. for C₁₆H₁₄FN₃O, 283.1; m/z found, 284.2 [M+H]⁺. ¹HNMR (500 MHz, DMSO-d₆) δ 8.86-8.78 (m, 1H), 8.37-8.28 (m, 2H), 7.77-7.67(m, 1H), 7.67-7.59 (m, 1H), 7.28 (t, J=9.1 Hz, 1H), 5.51 (s, 2H),2.38-2.25 (m, 3H), 2.18 (s, 3H).

Example 25:1-[6-[3-(Difluoromethoxy)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]propan-2-one

The title compound was prepared in a manner analogous to Intermediate 3,using 1-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)propan-2-one(Intermediate 12) instead of 6-bromo-1H-pyrazolo[4,3-B]pyridine, and2-(3-(difluoromethoxy)-4-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolaneinstead of2-[3-(difluoromethyl)-4-fluoro-phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.MS (ESI): mass calcd. for C₁₆H₁₂F₃N₃O₂, 335.1; m/z found, 336.1 [M+H]⁺.¹H NMR (500 MHz, DMSO-d₆) δ 8.94-8.83 (m, 1H), 8.43-8.38 (m, 1H),8.39-8.35 (m, 1H), 7.87-7.79 (m, 1H), 7.78-7.70 (m, 1H), 7.63-7.56 (m,1H), 7.37 (t, J=73.2 Hz, 1H), 5.55 (s, 2H), 2.21 (s, 3H).

Example 26:1-[6-[4-Chloro-3-(difluoromethoxy)phenyl]pyrazolo[4,3-b]pyridin-1-yl]propan-2-one

The title compound was prepared in a manner analogous to Intermediate 3,using 1-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)propan-2-one(Intermediate 12) instead of 6-bromo-1H-pyrazolo[4,3-B]pyridine, and2-(3-(difluoromethoxy)-4-chlorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolaneinstead of2-[3-(difluoromethyl)-4-fluoro-phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.MS (ESI): mass calcd. for C₁₆H₁₂ClF₂N₃O₂, 351.1; m/z found, 352.1[M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 8.92 (d, J=1.9 Hz, 1H), 8.46-8.41(m, 1H), 8.41-8.35 (m, 1H), 7.83-7.79 (m, 1H), 7.77 (d, J=8.6 Hz, 1H),7.72 (dd, J=8.4, 2.0 Hz, 1H), 7.43 (t, J=73.2 Hz, 1H), 5.56 (s, 2H),2.21 (s, 3H).

Example 27:1-[6-(5-Chloro-2-thienyl)pyrazolo[4,3-b]pyridin-1-yl]butan-2-one

The title compound was prepared in a manner analogous to Example 1 using5-chlorothiophene-2-boronic acid instead of 3,5-difluorophenylboronicacid. MS (ESI): mass calcd. for C₁₄H₁₂CN₃S, 305.0; m/z found, 306.0[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.86 (d, J=1.8 Hz, 1H), 8.35-8.33(m, 1H), 8.30-8.28 (m, 1H), 7.59 (d, J=4.0 Hz, 1H), 7.25 (d, J=4.0 Hz,1H), 5.52 (s, 2H), 2.58 (q, J=7.3 Hz, 2H), 0.98 (t, J=7.3 Hz, 3H).

Example 28: 1-[6-(4-Fluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]butan-2-one

The title compound was prepared in a manner analogous to Example 1 using4-fluorophenylboronic acid instead of 3,5-difluorophenylboronic acid. MS(ESI): mass calcd. for C₁₆H₁₄FN₃O, 283.1; m/z found, 284.0 [M+H]⁺. ¹HNMR (400 MHz, DMSO-d₆) δ 8.85 (d, J=1.9 Hz, 1H), 8.36-8.34 (m, 2H),7.88-7.81 (m, 2H), 7.42-7.34 (m, 2H), 5.53 (s, 2H), 2.57 (q, J=7.3 Hz,2H), 0.97 (t, J=7.2 Hz, 3H).

Example 29: 1-[6-(3-Fluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]butan-2-one

The title compound was prepared in a manner analogous to Example 1 using3-fluorophenylboronic acid instead of 3,5-difluorophenylboronic acid. MS(ESI): mass calcd. for C₁₆H₁₄FN₃O, 283.1; m/z found, 284.1 [M+H]⁺. ¹HNMR (400 MHz, DMSO-d₆) δ 8.91 (d, J=1.9 Hz, 1H), 8.44-8.42 (m, 1H),8.38-8.35 (m, 1H), 7.72-7.65 (m, 2H), 7.62-7.55 (m, 1H), 7.32-7.25 (m,1H), 5.54 (s, 2H), 2.57 (q, J=7.3 Hz, 2H), 0.98 (t, J=7.3 Hz, 3H).

Example 30:1-[6-[3-(Difluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]butan-2-one

The title compound was prepared in a manner analogous to Example 1 using3-difluoromethyl-phenylboronic acid instead of 3,5-difluorophenylboronicacid. MS (ESI): mass calcd. for C₁₇H₁₅F₂N₃O, 315.1; m/z found, 316.0[M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 8.90 (d, J=1.9 Hz, 1H), 8.44-8.42(m, 1H), 8.38-8.36 (m, 1H), 8.01-7.97 (m, 2H), 7.73-7.64 (m, 2H), 7.13(t, J=55.8 Hz, 1H), 5.55 (s, 2H), 2.57 (q, J=7.3 Hz, 2H), 0.98 (t, J=7.3Hz, 3H).

Example 31:1-[6-[3-(1,1-Difluoroethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]butan-2-one

The title compound was prepared in a manner analogous to Intermediate11, using 6-(3-(1,1-difluoroethyl)phenyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 7) instead of bromo-1H-pyrazolo[4,3-B]pyridine. MS (ESI):mass calcd. for C₁₈H₁₇F₂N₃O, 329.1; m/z found, 330.2 [M+H]⁺. ¹H NMR (500MHz, DMSO-d₆) δ 8.91 (d, J=2.0 Hz, 1H), 8.44-8.40 (m, 1H), 8.39-8.36 (m,1H), 7.96-7.91 (m, 2H), 7.69-7.62 (m, 2H), 5.55 (s, 2H), 2.57 (q, J=7.3Hz, 2H), 2.06 (t, J=18.9 Hz, 3H), 0.98 (t, J=7.3 Hz, 3H).

Example 32:1-[6-(4-Fluoro-3-methyl-phenyl)pyrazolo[4,3-b]pyridin-1-yl]butan-2-oneTrifluoroacetate Salt

The title compound was prepared in a manner analogous to Intermediate11, using 6-(4-fluoro-3-methylphenyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 2) instead of 6-bromo-1H-pyrazolo[4,3-B]pyridine. MS(ESI): mass calcd. for C₁₇H₁₆FN₃O, 297.1; m/z found, 299.1 [M+H]⁺. ¹HNMR (500 MHz, MeOD) δ 8.87-8.84 (m, 1H), 8.34-8.32 (m, 1H), 8.31-8.29(m, 1H), 7.68-7.63 (m, 1H), 7.61-7.55 (m, 1H), 7.22-7.16 (m, 1H), 5.50(s, 2H), 2.63 (q, J=7.4 Hz, 2H), 2.38-2.36 (m, 3H), 1.09 (t, J=7.3 Hz,3H).

Example 33:1-[6-(2,3-Difluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]butan-2-one

The title compound was prepared in a manner analogous to Example 1 using2,3-difluorophenylboronic acid instead of 3,5-difluorophenylboronicacid. MS (ESI): mass calcd. for C₁₆H₁₃F₂N₃O, 301.1; m/z found, 302.0[M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 8.73 (t, J=1.9 Hz, 1H), 8.40 (d,J=1.0 Hz, 1H), 8.34-8.33 (m, 1H), 7.58-7.51 (m, 1H), 7.50-7.45 (m, 1H),7.41-7.36 (m, 1H), 5.55 (s, 2H), 2.57 (q, J=7.3 Hz, 2H), 0.97 (t, J=7.3Hz, 3H).

Example 34:1-[6-(3,4-Difluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]butan-2-one

The title compound was prepared in a manner analogous to Example 1 using3,4-difluorophenylboronic acid instead of 3,5-difluorophenylboronicacid. MS (ESI): mass calcd. for C₁₆H₁₃F₂N₃O, 301.1; m/z found, 302.0[M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 8.90 (d, J=2.0 Hz, 1H), 8.43-8.41(m, 1H), 8.36 (d, J=1.0 Hz, 1H), 7.98-7.92 (m, 1H), 7.72-7.67 (m, 1H),7.66-7.58 (m, 1H), 5.53 (s, 2H), 2.57 (q, J=7.3 Hz, 2H), 0.98 (t, J=7.3Hz, 3H).

Example 35:1-[6-(3,4-Difluorophenyl)-3-fluoro-pyrazolo[4,3-b]pyridin-1-yl]butan-2-one

The title compound was prepared in a manner analogous to Intermediate 3,using 1-(6-bromo-3-fluoro-1H-pyrazolo[4,3-b]pyridin-1-yl)butan-2-one(Intermediate 15) instead of6-bromo-3-methyl-1H-pyrazolo[4,3-b]pyridine, and3,4-difluorophenylboronic acid instead of2-(3-(difluoromethyl)-4-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.MS (ESI): mass calcd. for C₁₆H₁₂F₃N₃O, 319.1; m/z found, 320.3 [M+H]⁺.¹H NMR (500 MHz, DMSO-d₆) δ 8.94 (d, J=1.8 Hz, 1H), 8.47-8.41 (m, 1H),8.00-7.92 (m, 1H), 7.73-7.68 (m, 1H), 7.64 (dt, J=10.5, 8.5 Hz, 1H),5.42 (s, 2H), 2.57 (q, J=7.3 Hz, 2H), 0.98 (t, J=7.3 Hz, 3H).

Example 36:1-(6-(3-(Difluoromethyl)-4-fluorophenyl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-1-yl)butan-2-one

The title compound was prepared in a manner analogous to Intermediate11, using6-(3-(difluoromethyl)-4-fluorophenyl)-3-methyl-1H-pyrazolo[4,3-b]pyridine(Intermediate 10) instead of 6-bromo-1H-pyrazolo[4,3-B]pyridine. MS(ESI): mass calcd. for C₁₈H₁₆F₃N₃O, 347.1; m/z found, 348.1 [M+H]⁺. ¹HNMR (400 MHz, CDCl₃) δ 8.75 (d, J=1.9 Hz, 1H), 7.83 (d, J=6.5 Hz, 1H),7.76-7.68 (m, 1H), 7.64 (d, J=1.9 Hz, 1H), 7.26 (s, 1H), 6.98 (t, J=54.9Hz, 1H), 5.14 (s, 2H), 2.71 (s, 3H), 2.47 (q, J=7.3 Hz, 2H), 1.09 (t,J=7.3 Hz, 3H).

Example 37:1-[6-[3-(1,1-Difluoroethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]butan-2-one

The title compound was prepared in a manner analogous to Intermediate11, using6-(3-(1,1-difluoroethyl)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 6) instead of 6-bromo-1H-pyrazolo[4,3-B]pyridine. MS(ESI): mass calcd. for C₁₈H₁₆F₃N₃O, 347.1; m/z found, 348.1 [M+H]⁺. ¹HNMR (500 MHz, DMSO-d₆) δ 8.89 (d, J=1.9 Hz, 1H), 8.43-8.39 (m, 1H),8.38-8.36 (m, 1H), 8.02-7.96 (m, 1H), 7.92 (dd, J=7.1, 2.4 Hz, 1H), 7.55(dd, J=11.0, 8.6 Hz, 1H), 5.55 (s, 2H), 2.57 (q, J=7.3 Hz, 2H), 2.09 (t,J=19.1 Hz, 3H), 0.97 (t, J=7.3 Hz, 3H).

Example 38:1-[6-[2-Fluoro-3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]butan-2-one

The title compound was prepared in a manner analogous to Example 1 using(2-fluoro-3-(trifluoromethyl)phenyl)boronic acid instead of3,5-difluorophenylboronic acid. MS (ESI): mass calcd. for C₁₇H₁₃F₄N₃O,351.1; m/z found, 352.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.73 (t,J=1.8 Hz, 1H), 8.42-8.40 (m, 1H), 8.38-8.36 (m, 1H), 8.03-7.97 (m, 1H),7.93-7.86 (m, 1H), 7.59 (t, J=7.8 Hz, 1H), 5.56 (s, 2H), 2.57 (q, J=7.3Hz, 2H), 0.97 (t, J=7.3 Hz, 3H).

Example 39:1-[6-[4-Fluoro-3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]butan-2-one

The title compound was prepared in a manner analogous to Example 1 using(4-fluoro-3-(trifluoromethyl)phenyl)boronic acid instead of3,5-difluorophenylboronic acid. MS (ESI): mass calcd. for C₁₇H₁₃F₄N₃O,351.1; m/z found, 352.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.92 (d,J=2.0 Hz, 1H), 8.48-8.45 (m, 1H), 8.40-8.38 (m, 1H), 8.23-8.13 (m, 2H),7.75-7.67 (m, 1H), 5.54 (s, 2H), 2.57 (q, J=7.3 Hz, 2H), 0.98 (t, J=7.3Hz, 3H).

Example 40:1-[6-[3-(Difluoromethoxy)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]butan-2-one

The title compound was prepared in a manner analogous to Intermediate11, using6-(3-(difluoromethoxy)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 4) instead of 6-bromo-1H-pyrazolo[4,3-B]pyridine. MS(ESI): mass calcd. for C₁₇H₁₄F₃N₃O₂, 349.1; m/z found, 350.2 [M+H]⁺. ¹HNMR (500 MHz, DMSO-d₆) δ 8.88 (d, J=2.0 Hz, 1H), 8.41-8.38 (m, 1H),8.38-8.35 (m, 1H), 7.82 (dd, J=7.7, 2.2 Hz, 1H), 7.77-7.71 (m, 1H), 7.59(dd, J=10.5, 8.6 Hz, 1H), 7.36 (t, J=73.2 Hz, 1H), 5.53 (s, 2H), 2.56(q, J=7.3 Hz, 2H), 0.98 (t, J=7.3 Hz, 3H).

Example 41:1-[6-[4-Chloro-3-(difluoromethoxy)phenyl]pyrazolo[4,3-b]pyridin-1-yl]butan-2-one

The title compound was prepared in a manner analogous to Intermediate11, using6-(4-chloro-3-(difluoromethoxy)phenyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 5) instead of 6-bromo-1H-pyrazolo[4,3-B]pyridine. MS(ESI): mass calcd. for C₁₇H₁₄ClF₂N₃O₂, 365.1; m/z found, 366.1 [M+H]⁺.¹H NMR (300 MHz, DMSO-d₆) δ 8.92 (d, J=1.9 Hz, 1H), 8.46-8.41 (m, 1H),8.41-8.36 (m, 1H), 7.84-7.76 (m, 2H), 7.72 (dd, J=8.4, 1.9 Hz, 1H), 7.44(t, J=73.2 Hz, 1H), 5.55 (s, 2H), 2.57 (q, J=7.5 Hz, 2H), 0.98 (t, J=7.2Hz, 3H).

Example 42:1-[6-(3,4,5-Trifluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]butan-2-one

The title compound was prepared in a manner analogous to Example 1 using3,4,5-trifluorophenylboronic acid instead of 3,5-difluorophenylboronicacid. MS (ESI): mass calcd. for C₁₆H₁₂F₃N₃O, 319.1; m/z found, 320.0[M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 8.94 (d, J=2.0 Hz, 1H), 8.48-8.46(m, 1H), 8.38 (d, J=1.0 Hz, 1H), 7.91-7.84 (m, 2H), 5.53 (s, 2H), 2.58(q, J=7.3 Hz, 2H), 0.98 (t, J=7.3 Hz, 3H).

Example 43:1-[6-(2,3,4-Trifluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]butan-2-one

The title compound was prepared in a manner analogous to Example 1 using2,3,4-trifluorophenylboronic acid instead of 3,5-difluorophenylboronicacid. MS (ESI): mass calcd. for C₁₆H₁₂F₃N₃O, 319.1; m/z found, 320.0[M+H]⁺.

Example 44: 3-Methyl-1-(6-phenylpyrazolo[4,3-b]pyridin-1-yl)butan-2-one

The title compound was prepared in a manner analogous to Example 1 using1-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)-3-methylbutan-2-one(Intermediate 13) instead of1-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)butan-2-one (Intermediate 11),and phenylboronic acid instead of 3,5-difluorophenylboronic acid. MS(ESI): mass calcd. for C₁₇H₁₇N₃O, 279.1; m/z found, 280.1 [M+H]⁺. ¹H NMR(400 MHz, DMSO) δ 8.87 (d, J=1.9 Hz, 1H), 8.35-8.32 (m, 2H), 7.83-7.77(m, 2H), 7.58-7.52 (m, 2H), 7.49-7.43 (m, 1H), 5.65 (s, 2H), 2.89-2.78(m, 1H), 1.13 (d, J=6.9 Hz, 6H).

Example 45:1-[6-(4-Fluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]-3-methyl-butan-2-one

The title compound was prepared in a manner analogous to Example 1 using1-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)-3-methylbutan-2-one(Intermediate 13) instead of1-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)butan-2-one (Intermediate 11),and 4-fluorophenylboronic acid instead of 3,5-difluorophenylboronicacid. MS (ESI): mass calcd. for C₁₇H₁₆FN₃O, 297.1; m/z found, 298.0[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.86 (d, J=1.9 Hz, 1H), 8.36-8.31(m, 2H), 7.88-7.81 (m, 2H), 7.43-7.35 (m, 2H), 5.65 (s, 2H), 2.89-2.77(m, 1H), 1.13 (d, J=6.9 Hz, 6H).

Example 46:1-[6-(3-Fluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]-3-methyl-butan-2-one

The title compound was prepared in a manner analogous to Example 1 using1-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)-3-methylbutan-2-one(Intermediate 13) instead of1-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)butan-2-one (Intermediate 11),and 3-fluorophenylboronic acid instead of 3,5-difluorophenylboronicacid. MS (ESI): mass calcd. for C₁₇H₁₆FN₃O, 297.1; m/z found, 298.1[M+H]⁺.

Example 47:1-[6-[3-(Difluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]-3-methyl-butan-2-one

The title compound was prepared in a manner analogous to Example 1 using1-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)-3-methylbutan-2-one(Intermediate 13) instead of1-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)butan-2-one (Intermediate 11),and (3-(difluoromethyl)phenyl)boronic acid instead of3,5-difluorophenylboronic acid. MS (ESI): mass calcd. for C₁₈H₁₇F₂N₃O,329.1; m/z found, 330.1 [M+H]⁺.

Example 48:1-[6-(2,3-Difluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]-3-methyl-butan-2-one

The title compound was prepared in a manner analogous to Example 1 using1-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)-3-methylbutan-2-one(Intermediate 13) instead of1-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)butan-2-one (Intermediate 11),and 2,3-difluorophenylboronic acid instead of 3,5-difluorophenylboronicacid. MS (ESI): mass calcd. for C₁₇H₁₅F₂N₃O, 315.1; m/z found, 316.0[M+H]⁺.

Example 49:1-[6-(3,4-Difluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]-3-methyl-butan-2-one

The title compound was prepared in a manner analogous to Example 1 using1-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)-3-methylbutan-2-one(Intermediate 13) instead of1-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)butan-2-one (Intermediate 11),and 3,4-difluorophenylboronic acid instead of 3,5-difluorophenylboronicacid. MS (ESI): mass calcd. for C₁₇H₁₅F₂N₃O, 315.1; m/z found, 316.0[M+H]⁺.

Example 50:1-[6-[2-Fluoro-3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]-3-methyl-butan-2-one

The title compound was prepared in a manner analogous to Example 1 using1-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)-3-methylbutan-2-one(Intermediate 13) instead of1-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)butan-2-one (Intermediate 11),and (2-fluoro-3-(trifluoromethyl)phenyl)boronic acid instead of3,5-difluorophenylboronic acid. MS (ESI): mass calcd. for C₁₈H₁₅F₄N₃O,365.1; m/z found, 366.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.73 (t,J=1.8 Hz, 1H), 8.43-8.39 (m, 1H), 8.37-8.33 (m, 1H), 8.03-7.97 (m, 1H),7.93-7.87 (m, 1H), 7.63-7.56 (m, 1H), 5.67 (s, 2H), 2.87-2.77 (m, 1H),1.12 (d, J=6.9 Hz, 6H).

Example 51:1-[6-[4-Fluoro-3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]-3-methyl-butan-2-one

The title compound was prepared in a manner analogous to Example 1 using1-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)-3-methylbutan-2-one(Intermediate 13) instead of1-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)butan-2-one (Intermediate 11),and (4-fluoro-3-(trifluoromethyl)phenyl)boronic acid instead of3,5-difluorophenylboronic acid. MS (ESI): mass calcd. for C₁₈H₁₅F₄N₃O,365.1; m/z found, 366.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.92 (d,J=2.0 Hz, 1H), 8.45-8.41 (m, 1H), 8.40-8.37 (m, 1H), 8.21-8.12 (m, 2H),7.76-7.67 (m, 1H), 5.65 (s, 2H), 2.88-2.78 (m, 1H), 1.13 (d, J=6.9 Hz,6H).

Example 52:1-[6-(4-Fluoro-2-methyl-phenyl)pyrazolo[4,3-b]pyridin-1-yl]-3-methyl-butan-2-one

The title compound was prepared in a manner analogous to Example 1 using1-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)-3-methylbutan-2-one(Intermediate 13) instead of1-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)butan-2-one (Intermediate 11),and 4-fluoro-2-methylphenylboronic acid instead of3,5-difluorophenylboronic acid. MS (ESI): mass calcd. for C₁₈H₁₈FN₃O,311.1; m/z found, 312.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO) δ 8.51 (d, J=1.8Hz, 1H), 8.39-8.33 (m, 1H), 8.08-8.02 (m, 1H), 7.39-7.32 (m, 1H),7.29-7.21 (m, 1H), 7.20-7.12 (m, 1H), 5.62 (s, 2H), 2.86-2.74 (m, 1H),2.26 (s, 3H), 1.10 (d, J=7.0 Hz, 6H).

Example 53:3-Methyl-1-[6-(3,4,5-trifluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]butan-2-one

The title compound was prepared in a manner analogous to Example 1 using1-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)-3-methylbutan-2-one(intermediate 13) instead of1-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)butan-2-one (Intermediate 11),and 3,4,5-trifluorophenylboronic acid instead of3,5-difluorophenylboronic acid. MS (ESI): mass calcd. for C₁₇H₁₄F₃N₃O,333.1; m/z found, 334.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.93 (d,J=2.0 Hz, 1H), 8.46-8.44 (m, 1H), 8.39-8.37 (m, 1H), 7.92-7.82 (m, 2H),5.64 (s, 2H), 2.90-2.79 (m, 1H), 1.13 (d, J=6.9 Hz, 6H).

Example 54:3-Methyl-1-[6-(2,3,4-trifluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]butan-2-one

The title compound was prepared in a manner analogous to Example 1 using1-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)-3-methylbutan-2-one(Intermediate 13) instead of1-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)butan-2-one (Intermediate 11),and 2,3,4-trifluorophenylboronic acid instead of3,5-difluorophenylboronic acid. MS (ESI): mass calcd. for C₁₇H₁₄F₃N₃O,333.1; m/z found, 334.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.71 (t,J=1.9 Hz, 1H), 8.40 (d, J=1.0 Hz, 1H), 8.31-8.28 (m, 1H), 7.57-7.48 (m,2H), 5.66 (s, 2H), 2.88-2.77 (m, 1H), 1.12 (d, J=7.0 Hz, 6H).

Example 55:2-[6-(5-Chloro-2-thienyl)pyrazolo[4,3-b]pyridin-1-yl]-1-cyclopropyl-ethanone

The title compound was prepared in a manner analogous to Example 1 using2-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)-1-cyclopropylethan-1-one(Intermediate 14) instead of1-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)butan-2-one (Intermediate 11),and 2-(5-chlorothiophen-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolaneinstead of 3,5-difluorophenylboronic acid. MS (ESI): mass calcd. forC₁₅H₁₂ClN₃S, 317.0; m/z found, 317.9 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ8.86 (d, J=1.9 Hz, 1H), 8.36-8.31 (m, 2H), 7.61 (d, J=4.0 Hz, 1H), 7.26(d, J=3.9 Hz, 1H), 5.69 (s, 2H), 2.15-2.07 (m, 1H), 1.05-0.91 (m, 4H).

Example 56:1-Cyclopropyl-2-[6-(5-methyl-2-thienyl)pyrazolo[4,3-b]pyridin-1-yl]ethanone

The title compound was prepared in a manner analogous to Example 1 using2-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)-1-cyclopropylethan-1-one(Intermediate 14) instead of1-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)butan-2-one (Intermediate 11),and 4,4,5,5-tetramethyl-2-(5-methylthiophen-2-yl)-1,3,2-dioxaborolaneinstead of 3,5-difluorophenylboronic acid. MS (ESI): mass calcd. forC₁₆H₁₅N₃S, 297.1; m/z found, 298.0 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ8.83 (d, J=1.9 Hz, 1H), 8.30 (d, J=1.0 Hz, 1H), 8.24-8.22 (m, 1H), 7.51(d, J=3.5 Hz, 1H), 6.92-6.89 (m, 1H), 5.68 (s, 2H), 2.14-2.07 (m, 1H),1.04-0.90 (m, 4H).

Example 57:1-Cyclopropyl-2-[6-(3-fluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]ethanone

The title compound was prepared in a manner analogous to Example 1 using2-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)-1-cyclopropylethan-1-one(Intermediate 14) instead of1-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)butan-2-one (Intermediate 11),and 3-fluorophenylboronic acid instead of 3,5-difluorophenylboronicacid. MS (ESI): mass calcd. for C₁₇H₁₄FN₃O, 295.1; m/z found, 296.0[M+H]⁺. ¹H NMR (400 MHz, DMSO) δ 8.92 (d, J=2.0 Hz, 1H), 8.50-8.47 (m,1H), 8.38-8.36 (m, 1H), 7.73-7.66 (m, 2H), 7.62-7.55 (m, 1H), 7.32-7.26(m, 1H), 5.71 (s, 2H), 2.15-2.07 (m, 1H), 1.04-0.91 (m, 4H).

Example 58:1-Cyclopropyl-2-[6-(2-fluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]ethanone

The title compound was prepared in a manner analogous to Example 1 using2-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)-1-cyclopropylethan-1-one(Intermediate 14) instead of1-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)butan-2-one (Intermediate 11),and 2-fluorophenylboronic acid instead of 3,5-difluorophenylboronicacid. MS (ESI): mass calcd. for C₁₇H₁₄FN₃O, 295.1; m/z found, 296.0[M+H]⁺. ¹H NMR (500 MHz, DMSO) δ 8.71 (t, J=2.0 Hz, 1H), 8.38 (d, J=1.0Hz, 1H), 8.31-8.29 (m, 1H), 7.68-7.63 (m, 1H), 7.54-7.49 (m, 1H),7.43-7.36 (m, 2H), 5.72 (s, 2H), 2.13-2.07 (m, 1H), 1.02-0.90 (m, 4H).

Example 59:1-Cyclopropyl-2-[6-(4-fluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]ethanone

The title compound was prepared in a manner analogous to Intermediate11, using 6-(4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridine (Intermediate 9)instead of 6-bromo-1H-pyrazolo[4,3-B]pyridine, and2-bromo-1-cyclopropylethanone instead of 1-bromo-2-butanone. MS (ESI):mass calcd. for C₁₇H₁₄FN₃O, 295.1; m/z found, 296.1 [M+H]⁺. ¹H NMR (500MHz, DMSO-d₆) δ 8.85 (d, J=1.9 Hz, 1H), 8.39-8.37 (m, 1H), 8.35-8.34 (m,1H), 7.88-7.83 (m, 2H), 7.41-7.35 (m, 2H), 5.70 (s, 2H), 2.14-2.07 (m,1H), 1.02-0.91 (m, 4H).

Example 60:1-Cyclopropyl-2-[6-(m-tolyl)pyrazolo[4,3-b]pyridin-1-yl]ethanone

The title compound was prepared in a manner analogous to Example 1 using2-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)-1-cyclopropylethan-1-one(Intermediate 14) instead of1-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)butan-2-one (Intermediate 11),and 3-methylphenylboronic acid instead of 3,5-difluorophenylboronicacid. MS (ESI): mass calcd. for C₁₈H₁₇N₃O, 291.1; m/z found, 292.1[M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 8.86 (d, J=1.9 Hz, 1H), 8.39-8.36(m, 1H), 8.36-8.33 (m, 1H), 7.64-7.61 (m, 1H), 7.61-7.57 (m, 1H), 7.42(t, J=7.6 Hz, 1H), 7.29-7.24 (m, 1H), 5.71 (s, 2H), 2.41 (s, 3H),2.14-2.06 (m, 1H), 1.04-0.90 (m, 4H).

Example 61:1-Cyclopropyl-2-[6-[3-(difluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]ethanone

The title compound was prepared in a manner analogous to Example 1 using2-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)-1-cyclopropylethan-1-one(Intermediate 14) instead of1-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)butan-2-one (Intermediate 11),and (3-(difluoromethyl)phenyl)boronic acid instead of3,5-difluorophenylboronic acid. MS (ESI): mass calcd. for C₁₈H₁₅F₂N₃O,327.1; m/z found, 328.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO) δ 8.90 (d, J=2.0Hz, 1H), 8.49-8.46 (m, 1H), 8.39-8.36 (m, 1H), 8.03-7.96 (m, 2H),7.73-7.63 (m, 2H), 7.13 (t, J=55.7 Hz, 1H), 5.73 (s, 2H), 2.15-2.07 (m,1H), 1.04-0.91 (m, 4H).

Example 62:1-Cyclopropyl-2-[6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]ethanone

The title compound was prepared in a manner analogous to Example 1 using2-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)-1-cyclopropylethan-1-one(Intermediate 14) instead of1-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)butan-2-one (Intermediate 11),and 3-(trifluoromethyl)phenylboronic acid instead of3,5-difluorophenylboronic acid. MS (ESI): mass calcd. for C₁₈H₁₄F₃N₃O,345.1; m/z found, 346.0 [M+H]⁺. ¹H NMR (500 MHz, DMSO) δ 9.05-8.86 (d,J=2.1 Hz, 1H), 8.60-8.47 (t, J=1.6 Hz, 1H), 8.44-8.32 (d, J=1.1 Hz, 1H),8.21-8.07 (d, J=6.5 Hz, 2H), 7.91-7.69 (m, 2H), 5.84-5.57 (s, 2H),2.19-1.99 (d, J=4.5 Hz, 1H), 1.13-0.78 (m, 6H).

Example 63:1-Cyclopropyl-2-[6-[3-(trifluoromethoxy)phenyl]pyrazolo[4,3-b]pyridin-1-yl]ethanone

The title compound was prepared in a manner analogous to Example 1 using2-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)-1-cyclopropylethan-1-one(Intermediate 14) instead of1-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)butan-2-one (Intermediate 11),3-(trifluoromethoxy)phenylboronic acid instead of3,5-difluorophenylboronic acid, and RuPhos Pd G3 instead ofPd(dppf)C₁₂.DCM. MS (ESI): mass calcd. for C₁₈H₁₄F₃N₃O₂, 361.1; m/zfound, 362.1 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.82 (d, J=1.9 Hz, 1H),8.35 (d, J=1.0 Hz, 1H), 7.73 (dd, J=1.8, 1.0 Hz, 1H), 7.59-7.51 (m, 2H),7.47 (d, J=2.7 Hz, 1H), 7.32-7.29 (m, 1H), 5.37 (s, 2H), 1.90 (tt,J=7.8, 4.5 Hz, 1H), 1.20-1.13 (m, 2H), 1.02-0.95 (m, 2H).

Example 64:1-Cyclopropyl-2-[6-(2,3-difluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]ethanone

The title compound was prepared in a manner analogous to Example 1 using2-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)-1-cyclopropylethan-1-one(Intermediate 14) instead of1-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)butan-2-one (Intermediate 11),and 2,3-difluorophenylboronic acid instead of 3,5-difluorophenylboronicacid. MS (ESI): mass calcd. for C₁₇H₁₃F₂N₃O, 313.1; m/z found, 313.9[M+H]⁺. ¹H NMR (400 MHz, DMSO) δ 8.73 (t, J=1.9 Hz, 1H), 8.40 (d, J=1.0Hz, 1H), 8.37-8.35 (m, 1H), 7.59-7.45 (m, 2H), 7.43-7.35 (m, 1H), 5.73(s, 2H), 2.15-2.06 (m, 1H), 1.03-0.90 (m, 4H).

Example 65:1-Cyclopropyl-2-[6-(3,4-difluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]ethanone

The title compound was prepared in a manner analogous to Example 1 using2-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)-1-cyclopropylethan-1-one(Intermediate 14) instead of1-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)butan-2-one (Intermediate 11),and 3,4-difluorophenylboronic acid instead of 3,5-difluorophenylboronicacid. MS (ESI): mass calcd. for C₁₇H₁₃F₂N₃O, 313.1; m/z found, 314.0[M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 8.90 (d, J=1.9 Hz, 1H), 8.47-8.46(m, 1H), 8.37 (d, J=0.9 Hz, 1H), 7.96 (ddd, J=12.2, 7.8, 2.3 Hz, 1H),7.72-7.67 (m, 1H), 7.65-7.58 (m, 1H), 5.70 (s, 2H), 2.15-2.08 (m, 1H),1.03-0.92 (m, 4H).

Example 66:1-Cyclopropyl-2-[6-(3,5-difluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]ethanone

The title compound was prepared in a manner analogous to Example 1 using2-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)-1-cyclopropylethan-1-one(Intermediate 14) instead of1-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)butan-2-one (Intermediate 11).MS (ESI): mass calcd. for C₁₇H₁₃F₂N₃O, 313.1; m/z found, 314.0 [M+H]⁺.¹H NMR (400 MHz, DMSO) δ 8.95 (d, J=1.9 Hz, 1H), 8.56-8.54 (m, 1H),8.39-8.37 (m, 1H), 7.69-7.60 (m, 2H), 7.38-7.29 (m, 1H), 5.70 (s, 2H),2.17-2.08 (m, 1H), 1.04-0.91 (m, 4H).

Example 67:2-[6-(3-Chloro-2-fluoro-phenyl)pyrazolo[4,3-b]pyridin-1-yl]-1-cyclopropyl-ethanone

The title compound was prepared in a manner analogous to Example 1 using2-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)-1-cyclopropylethan-1-one(Intermediate 14) instead of1-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)butan-2-one (Intermediate 11),and 3-chloro-2-fluorophenylboronic acid instead of3,5-difluorophenylboronic acid. MS (ESI): mass calcd. for C₁₇H₁₃ClFN₃O,329.1; m/z found, 330.0 [M+H]⁺.

Example 68:2-[6-(3-Chloro-4-fluoro-phenyl)pyrazolo[4,3-b]pyridin-1-yl]-1-cyclopropyl-ethanone

The title compound was prepared in a manner analogous to Example 1 using2-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)-1-cyclopropylethan-1-one(Intermediate 14) instead of1-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)butan-2-one (Intermediate 11),and 3-chloro-4-fluorophenylboronic acid instead of3,5-difluorophenylboronic acid. MS (ESI): mass calcd. for C₁₇H₁₃ClFN₃O,329.1; m/z found, 330.0 [M+H]⁺.

Example 69:1-Cyclopropyl-2-[6-(4-fluoro-3-methyl-phenyl)pyrazolo[4,3-b]pyridin-1-yl]ethanone

The title compound was prepared in a manner analogous to Example 1 using2-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)-1-cyclopropylethan-1-one(Intermediate 14) instead of1-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)butan-2-one (Intermediate 11),and 4-fluoro-3-methylphenylboronic acid instead of3,5-difluorophenylboronic acid. MS (ESI): mass calcd. for C₁₈H₁₆FN₃O,309.1; m/z found, 310.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.85 (d,J=2.0 Hz, 1H), 8.39-8.36 (m, 1H), 8.35-8.33 (m, 1H), 7.78-7.73 (m, 1H),7.69-7.63 (m, 1H), 7.34-7.27 (m, 1H), 5.70 (s, 2H), 2.37-2.31 (m, 3H),2.14-2.06 (m, 1H), 1.03-0.90 (m, 4H).

Example 70:1-Cyclobutyl-2-[6-(4-fluoro-3-methyl-phenyl)pyrazolo[4,3-b]pyridin-1-yl]ethanone

The title compound was prepared in a manner analogous to Intermediate16, Step A, using 6-(4-fluoro-3-methylphenyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 2) instead of 6-bromo-1H-pyrazolo[4,3-B]pyridine, and2-bromo-1-cyclobutylethan-1-one (Intermediate 17) instead of(chloromethyl)(ethyl)sulfane. MS (ESI): mass calcd. for C₁₉H₁₈FN₃O,323.1; m/z found, 324.0 [M+H]⁺. ¹H NMR (400 MHz, Methanol-d₄) δ 8.80(br.s, 1H), 8.28-8.24 (m, 1H), 8.20-8.17 (m, 1H), 7.65-7.60 (m, 1H),7.59-7.53 (m, 1H), 7.22-7.14 (m, 1H), 5.41 (s, 2H), 3.55-3.45 (m, 1H),2.40-2.26 (m, 5H), 2.22-2.12 (m, 2H), 2.09-1.96 (m, 1H), 1.91-1.79 (m,1H).

Example 71:1-Cyclopropyl-2-[6-(2-fluoro-3-methyl-phenyl)pyrazolo[4,3-b]pyridin-1-yl]ethanone

The title compound was prepared in a manner analogous to Example 1 using2-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)-1-cyclopropylethan-1-one(Intermediate 14) instead of1-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)butan-2-one (Intermediate 11),and 2-fluoro-3-methylphenylboronic acid instead of3,5-difluorophenylboronic acid. MS (ESI): mass calcd. for C₁₈H₁₆FN₃O,309.1; m/z found, 310.1 [M+H]⁺.

Example 72:1-Cyclopropyl-2-[6-(4-fluoro-2-methyl-phenyl)pyrazolo[4,3-b]pyridin-1-yl]ethanone

The title compound was prepared in a manner analogous to Example 1 using2-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)-1-cyclopropylethan-1-one(Intermediate 14) instead of1-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)butan-2-one (Intermediate 11),and 4-fluoro-2-methylphenylboronic acid instead of3,5-difluorophenylboronic acid. MS (ESI): mass calcd. for C₁₈H₁₆FN₃O,309.1; m/z found, 310.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO) δ 8.51 (d, J=1.8Hz, 1H), 8.37-8.36 (m, 1H), 8.11-8.08 (m, 1H), 7.38-7.33 (m, 1H),7.27-7.22 (m, 1H), 7.19-7.13 (m, 1H), 5.68 (s, 2H), 2.27 (s, 3H),2.12-2.03 (m, 1H), 1.04-0.87 (m, 4H).

Example 73:1-Cyclopropyl-2-[6-[2-fluoro-3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]ethanone

The title compound was prepared in a manner analogous to Example 1 using2-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)-1-cyclopropylethan-1-one(Intermediate 14) instead of1-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)butan-2-one (Intermediate 11),and (2-fluoro-3-(trifluoromethyl)phenyl)boronic acid instead of3,5-difluorophenylboronic acid. MS (ESI): mass calcd. for C₁₈H₁₃F₄N₃O,363.1; m/z found, 363.9 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.75-8.71(m, 1H), 8.43-8.38 (m, 2H), 8.03-7.97 (m, 1H), 7.93-7.86 (m, 1H),7.63-7.56 (m, 1H), 5.74 (s, 2H), 2.15-2.06 (m, 1H), 1.04-0.89 (m, 4H).

Example 74:1-Cyclopropyl-2-[6-[4-fluoro-3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]ethanone

The title compound was prepared in a manner analogous to Example 1 using2-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)-1-cyclopropylethan-1-one(Intermediate 14) instead of1-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)butan-2-one (Intermediate 11),4-fluoro-3-(trifluoromethyl)phenylboronic acid instead of3,5-difluorophenylboronic acid, and RuPhos Pd G3 instead ofPd(dppf)C₁₂.DCM. MS (ESI): mass calcd. for C₁₈H₁₃F₄N₃O, 363.1; m/zfound, 364.0 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.79 (d, J=1.9 Hz, 1H),8.35 (d, J=1.0 Hz, 1H), 7.86-7.82 (m, 1H), 7.82-7.77 (m, 1H), 7.70 (dd,J=1.9, 1.0 Hz, 1H), 7.40-7.35 (m, 1H), 5.39 (s, 2H), 1.92 (tt, J=7.7,4.5 Hz, 1H), 1.19-1.14 (m, 2H), 1.02-0.97 (m, 2H).

Example 75:2-[6-[4-Chloro-3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1-cyclopropyl-ethanone

The title compound was prepared in a manner analogous to Example 1 using2-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)-1-cyclopropylethan-1-one(Intermediate 14) instead of1-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)butan-2-one (Intermediate 11),4-chloro-3-(trifluoromethyl)phenylboronic acid instead of3,5-difluorophenylboronic acid, and RuPhos Pd G3 instead ofPd(dppf)C₁₂.DCM. MS (ESI): mass calcd. for C₁₈H₁₃CF₃N₃O, 379.1; m/zfound, 380.0 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.80 (d, J=1.9 Hz, 1H),8.36 (d, J=1.0 Hz, 1H), 7.93 (d, J=2.2 Hz, 1H), 7.77-7.72 (m, 2H), 7.66(d, J=8.4 Hz, 1H), 5.39 (s, 2H), 1.96-1.88 (m, 1H), 1.19-1.14 (m, 2H),1.03-0.97 (m, 2H).

Example 76:1-Cyclopropyl-2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]ethanone

The title compound was prepared in a manner analogous to Intermediate16, Step A, using6-(3-(difluoromethyl)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 3) instead of 6-bromo-1H-pyrazolo[4,3-b]pyridine, and2-bromo-1-cyclopropylethanone instead of (chloromethyl)(ethyl)sulfane.MS (ESI): mass calcd. for C₁₈H₁₄F₃N₃O, 345.1; m/z found, 346.0 [M+H]⁺.¹H NMR (500 MHz, CDCl₃) δ 8.80 (d, J=1.9 Hz, 1H), 8.35 (d, J=1.0 Hz,1H), 7.86-7.82 (m, 1H), 7.75-7.70 (m, 2H), 7.31-7.27 (m, 1H), 6.98 (t,J=54.9 Hz, 1H), 5.38 (s, 2H), 1.91 (tt, J=7.8, 4.5 Hz, 1H), 1.19-1.14(m, 2H), 1.02-0.97 (m, 2H).

Example 77:1-Cyclopropyl-2-[6-[3-(difluoromethoxy)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]ethanone

The title compound was prepared in a manner analogous to Example 1 using2-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)-1-cyclopropylethan-1-one(Intermediate 14) instead of1-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)butan-2-one (Intermediate 11),2-(3-(difluoromethoxy)-4-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolaneinstead of 3,5-difluorophenylboronic acid, and RuPhos Pd G3 instead ofPd(dppf)Cl₂.DCM. MS (ESI): mass calcd. for C₁₈H₁₄F₃N₃O₂, 361.1; m/zfound, 362.1 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.78 (d, J=1.9 Hz, 1H),8.34 (d, J=1.0 Hz, 1H), 7.68 (dd, J=1.9, 1.0 Hz, 1H), 7.53-7.43 (m, 2H),7.34-7.30 (m, 1H), 6.64 (t, J=73.2 Hz, 1H), 5.37 (s, 2H), 1.90 (tt,J=7.8, 4.5 Hz, 1H), 1.19-1.12 (m, 2H), 1.03-0.95 (m, 2H).

Example 78:1-Cyclopropyl-2-[6-(4-fluoro-2,3-dimethyl-phenyl)pyrazolo[4,3-b]pyridin-1-yl]ethanone

The title compound was prepared in a manner analogous to Example 1 using2-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)-1-cyclopropylethan-1-one(Intermediate 14) instead of1-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)butan-2-one (Intermediate 11),and 4-fluoro-2,3-dimethylphenylboronic acid instead of3,5-difluorophenylboronic acid. MS (ESI): mass calcd. for C₁₉H₁₈FN₃O,323.1; m/z found, 324.0 [M+H]⁺.

Example 79:1-Cyclopropyl-2-[6-(2,3,4-trifluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]ethanone

The title compound was prepared in a manner analogous to Example 1 using2-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)-1-cyclopropylethan-1-one(Intermediate 14) instead of1-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)butan-2-one (Intermediate 11)and 2,3,4-trifluorophenylboronic acid instead of3,5-difluorophenylboronic acid. MS (ESI): mass calcd. for C₁₇H₁₂F₃N₃O,331.1; m/z found, 331.9 [M+H]⁺. ¹H NMR (400 MHz, DMSO) δ 8.73-8.69 (m,1H), 8.42-8.40 (m, 1H), 8.35 (s, 1H), 7.58-7.47 (m, 2H), 5.72 (s, 2H),2.15-2.06 (m, 1H), 1.05-0.89 (m, 4H).

Example 80:(RS)-1-(Ethylsulfinylmethyl)-6-(3-fluorophenyl)pyrazolo[4,3-b]pyridine

The title compound was prepared in a manner analogous to Intermediate 3,using 6-bromo-1-((ethylsulfinyl)methyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 16) instead of6-bromo-3-methyl-1H-pyrazolo[4,3-b]pyridine, and 3-fluorophenylboronicacid instead of2-(3-(difluoromethyl)-4-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.MS (ESI): mass calcd. for C₁₅H₁₄FN₃OS, 303.1; m/z found, 304.1 [M+H]⁺.¹H NMR (300 MHz, DMSO-d₆) δ 8.95 (d, J=1.9 Hz, 1H), 8.68-8.57 (m, 1H),8.51 (s, 1H), 7.77-7.65 (m, 2H), 7.66-7.54 (m, 1H), 7.38-7.24 (m, 1H),5.93 (d, J=13.7 Hz, 1H), 5.77 (d, J=13.6 Hz, 1H), 3.07-2.66 (m, 2H),1.25 (t, J=7.5 Hz, 3H).

Example 81:(RS)-1-(Ethylsulfinylmethyl)-6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridine

The title compound was prepared in a manner analogous to Intermediate 3,using 6-bromo-1-((ethylsulfinyl)methyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 16) instead of6-bromo-3-methyl-1H-pyrazolo[4,3-b]pyridine, and3-trifluoromethylphenylboronic acid instead of2-(3-(difluoromethyl)-4-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.MS (ESI): mass calcd. for C₁₆H₁₄F₃N₃S, 353.1; m/z found, 354.1 [M+H]⁺.¹H NMR (300 MHz, DMSO-d₆) δ 8.98 (d, J=1.9 Hz, 1H), 8.72-8.63 (m, 1H),8.52 (s, 1H), 8.21-8.08 (m, 2H), 7.89-7.76 (m, 2H), 5.95 (d, J=13.7 Hz,1H), 5.79 (d, J=13.7 Hz, 1H), 3.03-2.70 (m, 2H), 1.25 (t, J=7.5 Hz, 3H).

Example 82: (RS)6-(3,4-Difluorophenyl)-1-(ethylsulfinylmethyl)pyrazolo[4,3-b]pyridine

The title compound was prepared in a manner analogous to Intermediate 3,using 6-bromo-1-((ethylsulfinyl)methyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 16) instead of6-bromo-3-methyl-1H-pyrazolo[4,3-b]pyridine, and3,4-difluorophenylboronic acid instead of2-(3-(difluoromethyl)-4-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.MS (ESI): mass calcd. for C₁₅H₁₃F₂N₃S, 321.1; m/z found, 322.1 [M+H]⁺.¹H NMR (500 MHz, DMSO-d₆) δ 8.94 (d, J=2.0 Hz, 1H), 8.61 (dd, J=2.0, 1.0Hz, 1H), 8.50 (d, J=1.0 Hz, 1H), 7.99-7.91 (m, 1H), 7.73-7.61 (m, 2H),5.91 (d, J=13.7 Hz, 1H), 5.75 (d, J=13.7 Hz, 1H), 2.99-2.89 (m, 1H),2.85-2.76 (m, 1H), 1.25 (t, J=7.5 Hz, 3H).

Example 83:(RS)-6-(3-(Difluoromethyl)-4-fluorophenyl)-1-((ethylsulfinyl)methyl)-1H-pyrazolo[4,3-b]pyridine

The title compound was prepared in a manner analogous to Intermediate16, Steps A and B, using6-(3-(difluoromethyl)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 3) instead of 6-bromo-1H-pyrazolo[4,3-B]pyridine in StepA. MS (ESI): mass calcd. for C₁₆H₁₄F₃N₃OS, 353.1; m/z found, 354.1[M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 8.92 (d, J=2.0 Hz, 1H), 8.61 (dd,J=2.0, 1.0 Hz, 1H), 8.51 (d, J=1.0 Hz, 1H), 8.10-8.01 (m, 2H), 7.64-7.56(m, 1H), 7.31 (t, J=54.1 Hz, 1H), 5.93 (d, J=13.7 Hz, 1H), 5.77 (d,J=13.7 Hz, 1H), 2.99-2.89 (m, 1H), 2.85-2.76 (m, 1H), 1.25 (t, J=7.5 Hz,3H).

Example 84:(S*)-6-(3-(Difluoromethyl)-4-fluorophenyl)-1-((ethylsulfinyl)methyl)-1H-pyrazolo[4,3-b]pyridine

The title compound was prepared by the separation of Example 83 usingchiral SFC (Stationary phase: CHIRALPAK IC 5 μm 250*30 mm, Mobile phase:60% CO₂, 40% MeOH). MS (ESI): mass calcd. for C₁₆H₁₄F₃N₃OS, 353.1; m/zfound, 354.1 [M+H]⁺.

Example 85:(R*)-6-(3-(Difluoromethyl)-4-fluorophenyl)-1-((ethylsulfinyl)methyl)-1H-pyrazolo[4,3-b]pyridine

The title compound was prepared by the separation of Example 83 usingchiral SFC (Stationary phase: CHIRALPAK IC 5 μm 250*30 mm, Mobile phase:60% CO₂, 40% MeOH). MS (ESI): mass calcd. for C₁₆H₁₄F₃N₃OS, 353.1; m/zfound, 354.1 [M+H]⁺.

Example 86:(RS)-1-(Ethylsulfinylmethyl)-6-[2-fluoro-3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridine

The title compound was prepared in a manner analogous to Intermediate 3,using 6-bromo-1-((ethylsulfinyl)methyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 16) instead of6-bromo-3-methyl-1H-pyrazolo[4,3-b]pyridine, and2-fluoro-3-trifluoromethylphenylphenylboronic acid instead of2-(3-(difluoromethyl)-4-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.MS (ESI): mass calcd. for C₁₆H₁₃F₄N₃OS, 371.1; m/z found, 372.1 [M+H]⁺.¹H NMR (300 MHz, DMSO-d₆) δ 8.84-8.71 (m, 1H), 8.64-8.46 (m, 2H),8.06-7.96 (m, 1H), 7.96-7.87 (m, 1H), 7.61 (t, J=7.8 Hz, 1H), 5.95 (d,J=13.7 Hz, 1H), 5.78 (d, J=13.7 Hz, 1H), 3.02-2.86 (m, 1H), 2.87-2.72(m, 1H), 1.24 (t, J=7.5 Hz, 3H).

Example 87:(RS)-6-[4-Chloro-3-(difluoromethoxy)phenyl]-1-(ethylsulfinylmethyl)pyrazolo[4,3-b]pyridine

The title compound was prepared in a manner analogous to Intermediate 3,using 6-bromo-1-((ethylsulfinyl)methyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 16) instead of6-bromo-3-methyl-1H-pyrazolo[4,3-b]pyridine, and2-(3-(difluoromethoxy)-4-chlorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolaneinstead of2-(3-(difluoromethyl)-4-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.MS (ESI): mass calcd. for C₁₆H₁₄ClF₂N₃O₂S, 385.1; m/z found, 386.1[M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 8.95 (d, J=1.9 Hz, 1H), 8.66-8.57(m, 1H), 8.57-8.48 (m, 1H), 7.86-7.77 (m, 2H), 7.73 (dd, J=8.4, 2.0 Hz,1H), 7.45 (t, J=73.2 Hz, 1H), 5.94 (d, J=13.7 Hz, 1H), 5.77 (d, J=13.7Hz, 1H), 3.04-2.72 (m, 2H), 1.25 (t, J=7.5 Hz, 3H).

Example 88:(RS)-1-(Ethylsulfinylmethyl)-6-(3,4,5-trifluorophenyl)pyrazolo[4,3-b]pyridine

The title compound was prepared in a manner analogous to Intermediate 3,using 6-bromo-1-((ethylsulfinyl)methyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 16) instead of6-bromo-3-methyl-1H-pyrazolo[4,3-b]pyridine, and3,4,5-trifluorophenylboronic acid instead of2-(3-(difluoromethyl)-4-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.MS (ESI): mass calcd. for C₁₅H₁₂F₃N₃S, 339.1; m/z found, 340.1 [M+H]⁺.¹H NMR (500 MHz, DMSO-d₆) δ 8.97 (d, J=2.0 Hz, 1H), 8.67 (dd, J=2.0, 1.0Hz, 1H), 8.52 (d, J=1.0 Hz, 1H), 7.91-7.83 (m, 2H), 5.89 (d, J=13.6 Hz,1H), 5.74 (d, J=13.7 Hz, 1H), 2.99-2.89 (m, 1H), 2.86-2.76 (m, 1H), 1.25(t, J=7.5 Hz, 3H).

Example 89:6-(4-Fluoro-3-methyl-phenyl)-1-(2-methoxyethyl)pyrazolo[4,3-b]pyridineTrifluoroacetate Salt

The title compound was prepared in a manner analogous to Intermediate16, Step A, using 6-(4-fluoro-3-methylphenyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 2) instead of 6-bromo-1H-pyrazolo[4,3-B]pyridine, and2-bromoethyl methyl ether instead of (chloromethyl)(ethyl)sulfane. MS(ESI): mass calcd. for C₁₆H₁₆FN₃O, 285.1; m/z found, 286.0 [M+H]⁺.

Example 90:(RS)-4-Methoxy-1-[6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]butan-2-ol

The title compound was obtained from the treatment of Example 17((RS)-1-(oxetan-2-ylmethyl)-6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridine)with Agilent Bond Elut SCX cartridge. MS (ESI): mass calcd. forC₁₈H₁₈F₃N₃O₂, 365.1; m/z found, 366.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆)δ 8.90 (d, J=2.0 Hz, 1H), 8.54-8.51 (m, 1H), 8.34 (d, J=0.9 Hz, 1H),8.18-8.13 (m, 2H), 7.85-7.76 (m, 2H), 4.92 (d, J=5.8 Hz, 1H), 4.50-4.46(m, 2H), 4.08-3.98 (m, 1H), 3.47-3.40 (m, 2H), 3.20 (s, 3H), 1.74-1.64(m, 1H), 1.62-1.52 (m, 1H).

Example 91:(RS)-1-[6-(3,4-Difluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]butan-2-ol

The title compound was prepared in a manner analogous to Example 5 using1-(6-(3,4-difluorophenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)butan-2-one(Example 34) instead of1-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]butan-2-one.MS (ESI): mass calcd. for C₁₆H₁₅F₂N₃O, 303.1; m/z found, 304.0 [M+H]⁺.¹H NMR (500 MHz, CDCl₃) δ 8.67 (d, J=1.9 Hz, 1H), 8.17 (d, J=1.0 Hz,1H), 7.91 (dd, J=1.9, 1.0 Hz, 1H), 7.50-7.42 (m, 1H), 7.41-7.35 (m, 1H),7.35-7.29 (m, 1H), 4.52-4.45 (m, 1H), 4.34 (dd, J=14.2, 8.1 Hz, 1H),4.17-4.10 (m, 1H), 3.23 (br s, 1H), 1.70-1.57 (m, 2H), 1.10 (t, J=7.4Hz, 3H).

Example 92:(RS)-1-[6-[3-(Difluoromethoxy)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]butan-2-ol

The title compound was prepared in a manner analogous to Example 5 using1-(6-(3-(difluoromethoxy)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)butan-2-one(Example 40) instead of1-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]butan-2-one.MS (ESI): mass calcd. for C₁₇H₁₆F₃N₃O₂, 351.1; m/z found, 352.2 [M+H]⁺.¹H NMR (500 MHz, CDCl₃) 8.75 (d, J=1.9 Hz, 1H), 8.28 (d, J=1.0 Hz, 1H),7.91 (dd, J=1.9, 1.0 Hz, 1H), 7.54 (dd, J=7.3, 2.2 Hz, 1H), 7.52-7.48(m, 1H), 7.37-7.31 (dd, J=9.9, 8.5 Hz, 1H), 6.82-6.51 (t, J=73.2 Hz,1H), 4.53-4.48 (m, 1H), 4.40-4.33 (dd, J=14.1, 7.9 Hz, 1H), 4.17-4.10(m, 1H), 2.89-2.78 (br s, 1H), 1.70-1.60 (m, 2H), 1.12-1.06 (t, J=7.5Hz, 3H).

Example 93:(RS)-1-[6-[4-Chloro-3-(difluoromethoxy)phenyl]pyrazolo[4,3-b]pyridin-1-yl]butan-2-ol

The title compound was prepared in a manner analogous to Example 5 using1-[6-[4-chloro-3-(difluoromethoxy)phenyl]pyrazolo[4,3-b]pyridin-1-yl]butan-2-one(Example 41) instead of1-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]butan-2-one.MS (ESI): mass calcd. for C₁₇H₁₆ClF₂N₃O₂, 367.8; m/z found, 368.1[M+H]⁺. 1H NMR (500 MHz, CDCl₃) δ 8.72 (d, J=1.9 Hz, 1H), 8.24 (d, J=1.0Hz, 1H), 7.93 (dd, J=1.9, 1.0 Hz, 1H), 7.62-7.58 (m, 1H), 7.54-7.52 (m,1H), 7.50-7.46 (m, 1H), 6.65 (t, J=73.2 Hz, 1H), 4.53-4.48 (m, 1H), 4.36(dd, J=14.2, 7.9 Hz, 1H), 4.17-4.10 (m, 1H), 3.01 (s, 1H), 1.71-1.57 (m,2H), 1.10 (t, J=7.5 Hz, 3H).

Example 94:(RS)-1-[6-(3,4-Difluorophenyl)-3-fluoro-pyrazolo[4,3-b]pyridin-1-yl]butan-2-ol

The title compound was prepared in a manner analogous to Example 5 using1-[6-(3,4-difluorophenyl)-3-fluoro-pyrazolo[4,3-b]pyridin-1-yl]butan-2-one(Example 35) instead of1-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]butan-2-one.MS (ESI): mass calcd. for C₁₆H₁₄F₃N₃O, 321.1; m/z found, 322.0 [M+H]⁺.1H NMR (500 MHz, CDCl₃) δ 8.64 (d, J=1.8 Hz, 1H), 7.87-7.85 (m, 1H),7.48-7.42 (m, 1H), 7.39-7.30 (m, 2H), 4.34-4.28 (m, 1H), 4.25-4.18 (m,1H), 4.14-4.07 (m, 1H), 2.94 (d, J=4.2 Hz, 1H), 1.71-1.56 (m, 2H), 1.10(t, J=7.5 Hz, 3H).

Example 95:(RS)-1-[6-[3-(1,1-Difluoroethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]butan-2-ol

The title compound was prepared in a manner analogous to Example 5 using1-[6-[3-(1,1-difluoroethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]butan-2-one(Example 31) instead of1-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]butan-2-one.MS (ESI): mass calcd. for C₁₈H₁₉F₂N₃O, 331.1; m/z found, 332.1 [M+H]⁺.1H NMR (500 MHz, CDCl₃) δ 8.76 (d, J=1.9 Hz, 1H), 8.21 (d, J=1.0 Hz,1H), 7.97-7.95 (m, 1H), 7.80-7.77 (m, 1H), 7.73-7.69 (m, 1H), 7.61-7.56(m, 2H), 4.53-4.47 (m, 1H), 4.36 (dd, J=14.1, 8.0 Hz, 1H), 4.18-4.11 (m,1H), 3.25-3.20 (m, 1H), 2.01 (t, J=18.2 Hz, 3H), 1.69-1.59 (m, 2H), 1.10(t, J=7.5 Hz, 3H).

Example 96:(RS)-3-Methyl-1-(6-phenylpyrazolo[4,3-b]pyridin-1-yl)butan-2-ol

The title compound was prepared in a manner analogous to Example 3 using3-methyl-1-(6-phenylpyrazolo[4,3-b]pyridin-1-yl)butan-2-one (Example 44)instead of3-methyl-1-[6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]butan-2-one.MS (ESI): mass calcd. for C₁₇H₁₉N₃O, 281.2; m/z found, 282.1 [M+H]⁺. ¹HNMR (400 MHz, DMSO) δ 8.83 (d, J=1.9 Hz, 1H), 8.39-8.36 (m, 1H),8.30-8.29 (m, 1H), 7.85-7.79 (m, 2H), 7.58-7.52 (m, 2H), 7.49-7.43 (m,1H), 4.79 (d, J=5.9 Hz, 1H), 4.49-4.40 (m, 2H), 3.73-3.63 (m, 1H),1.70-1.57 (m, 1H), 0.97 (d, J=6.8 Hz, 3H), 0.94 (d, J=6.8 Hz, 3H).

Example 97:(RS)-3-Methyl-1-[6-(3,4,5-trifluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]butan-2-ol

The title compound was prepared in a manner analogous to Example 3 using3-methyl-1-[6-(3,4,5-trifluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]butan-2-one(Example 53) instead of3-methyl-1-[6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]butan-2-one.MS (ESI): mass calcd. for C₁₇H₁₆F₃N₃O, 335.1; m/z found, 336.0 [M+H]⁺.¹H NMR (400 MHz, DMSO) δ 8.88 (d, J=2.0 Hz, 1H), 8.51-8.48 (m, 1H),8.34-8.30 (m, 1H), 7.95-7.86 (m, 2H), 4.75 (d, J=6.0 Hz, 1H), 4.49-4.42(m, 2H), 3.74-3.65 (m, 1H), 1.70-1.57 (m, 1H), 0.97 (d, J=6.8 Hz, 3H),0.95 (d, J=6.8 Hz, 3H).

Example 98:1-(2,2-Difluorobutyl)-6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridine

To1-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]butan-2-one(Example 4) (64.0 mg, 0.19 mmol) stirring in DCM (2 mL) at 0° C. wasadded DAST (0.101 mL, 0.76 mmol). The reaction was slowly warmed to rt.After 23 h, the reaction was washed with a saturated solution of NaHCO₃,then the organic layer was dried, filtered, and concentrated underreduced pressure. The residue was purified by silica gel chromatography(hexanes\EtOAc 25 to 50%) afford the title compound as a yellow oil. MS(ESI): mass calcd. for C₁₇H₁₄F₅N₃, 355.1; m/z found, 356.1 [M+H]⁺. ¹HNMR (300 MHz, DMSO-d₆) δ 8.91 (d, J=1.9 Hz, 1H), 8.59-8.49 (m, 1H), 8.44(s, 1H), 8.13-8.00 (m, 2H), 7.64-7.53 (m, 1H), 7.31 (t, J=54.1 Hz, 1H),5.08 (t, J=13.9 Hz, 2H), 2.06-1.82 (m, 2H), 1.01 (t, J=7.5 Hz, 3H).

Example 99:1-(2,2-Difluorobutyl)-6-[3-(difluoromethoxy)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridine

The title compound was prepared in a manner analogous to Example 98using1-[6-[3-(difluoromethoxy)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]butan-2-one(Example 40) instead of1-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]butan-2-one.MS (ESI): mass calcd. for C₁₇H₁₄F₅N₃O, 371.1; m/z found, 372.1 [M+H]⁺.¹H NMR (500 MHz, DMSO-d₆) δ 8.92-8.89 (m, 1H), 8.53-8.48 (m, 1H), 8.43(s, 1H), 7.87-7.81 (m, 1H), 7.80-7.73 (m, 1H), 7.64-7.57 (m, 1H), 7.38(t, J=73.2 Hz, 1H), 5.07 (t, J=13.8 Hz, 2H), 2.01-1.86 (m, 2H), 1.01 (t,J=7.5 Hz, 3H).

Example 100:(RS)-1-Cyclopropyl-2-[6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]ethanol

The title compound was prepared in a manner analogous to Example 3 using1-cyclopropyl-2-[6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]ethanone(Example 62) instead of3-methyl-1-[6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]butan-2-one.MS (ESI): mass calcd. for C₁₈H₁₆F₃N₃O, 347.1; m/z found, 348.0 [M+H]⁺.¹H NMR (500 MHz, DMSO-d₆) δ 8.90 (d, J=1.9 Hz, 1H), 8.58-8.55 (m, 1H),8.32 (d, J=0.9 Hz, 1H), 8.19-8.14 (m, 2H), 7.85-7.75 (m, 2H), 4.94 (d,J=5.2 Hz, 1H), 4.58-4.54 (m, 2H), 3.41-3.32 (m, 1H), 0.92-0.81 (m, 1H),0.39-0.31 (m, 1H), 0.31-0.21 (m, 2H), 0.06-0.03 (m, 1H).

Example 101:(RS)-1-Cyclopropyl-2-[6-(4-fluoro-3-methyl-phenyl)pyrazolo[4,3-b]pyridin-1-yl]ethanol

The title compound was prepared in a manner analogous to Example 3 using1-cyclopropyl-2-[6-(4-fluoro-3-methyl-phenyl)pyrazolo[4,3-b]pyridin-1-yl]ethanone(Example 69) instead of3-methyl-1-[6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]butan-2-one.MS (ESI): mass calcd. for C₁₈H₁₈FN₃O, 311.1; m/z found, 312.1 [M+H]⁺. ¹HNMR (500 MHz, DMSO-d₆) δ 8.81 (d, J=1.9 Hz, 1H), 8.40-8.38 (m, 1H), 8.28(d, J=0.9 Hz, 1H), 7.79-7.76 (m, 1H), 7.70-7.65 (m, 1H), 7.33-7.28 (m,1H), 4.92 (d, J=5.2 Hz, 1H), 4.54-4.50 (m, 2H), 3.41-3.32 (m, 1H),2.36-2.33 (m, 3H), 0.91-0.81 (m, 1H), 0.39-0.19 (m, 3H), 0.05-0.02 (m,1H).

Example 102:(R)-1-Cyclopropyl-2-[6-(4-fluoro-3-methyl-phenyl)pyrazolo[4,3-b]pyridin-1-yl]ethanol

The title compound was prepared by the separation of Example 101 usingchiral SFC (Stationary phase: CHIRALPAK IC 5 μm 250×20 mm, Mobile phase:70% CO₂, 30% iPrOH). MS (ESI): mass calcd. for C₁₈H₁₈FN₃O, 311.1; m/zfound, 312.1 [M+H]⁺.

Example 103:(S)-1-Cyclopropyl-2-[6-(4-fluoro-3-methyl-phenyl)pyrazolo[4,3-b]pyridin-1-yl]ethanol

The title compound was prepared by the separation of Example 101 usingchiral SFC (Stationary phase: CHIRALPAK IC 5 μm 250×20 mm, Mobile phase:70% CO₂, 30% iPrOH). MS (ESI): mass calcd. for C₁₈H₁₈FN₃O, 311.1; m/zfound, 312.1 [M+H]⁺.

Example 104:(RS)-1-Cyclopropyl-2-(6-(3-(difluoromethyl)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)ethan-1-ol

The title compound was prepared in a manner analogous to Example 5 using1-cyclopropyl-2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]ethanone(Example 76) instead of1-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]butan-2-one.MS (ESI): mass calcd. for C₁₈H₁₆F₃N₃O, 347.1; m/z found, 348.1 [M+H]⁺.¹H NMR (500 MHz, DMSO-d₆) δ 8.84 (d, J=2.0 Hz, 1H), 8.51-8.44 (m, 1H),8.31 (d, J=1.0 Hz, 1H), 8.11-8.04 (m, 2H), 7.60-7.53 (m, 1H), 7.29 (t,J=54.1 Hz, 1H), 4.92 (d, J=5.1 Hz, 1H), 4.58-4.50 (m, 2H), 3.40-3.33 (m,1H), 0.91-0.83 (m, 1H), 0.40-0.31 (m, 1H), 0.30-0.21 (m, 2H), 0.05-0.03(m, 1H).

Example 105:(E/Z)-N-Methoxy-3-methyl-1-[6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]butan-2-imine

The title compound was prepared in a manner analogous to Example 6 usingo-methylhydroxylamine hydrochloride instead of hydroxylaminehydrochloride, and EtOH as a solvent. (ESI): mass calcd. forC₁₉H₁₉F₃N₄O, 376.2; m/z found, 377.1 [M+H]⁺.

Example 106:(E/Z)-1-Cyclopropyl-2-[6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]ethanoneoxime

The title compound was prepared in a manner analogous to Example 6 using1-cyclopropyl-2-[6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]ethanone(Example 62) instead of3-methyl-1-[6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]butan-2-one.MS (ESI): mass calcd. for C₁₈H₁₅F₃N₄O, 360.1; m/z found, 361.0 [M+H]⁺.

Example 107:(E/Z)-1-Cyclopropyl-2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]ethanoneOxime

The title compound was prepared in a manner analogous to Example 6 using1-cyclopropyl-2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]ethenone(Example 76) instead of3-methyl-1-[6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]butan-2-one,and triethylamine instead of Cs₂CO₃. MS (ESI): mass calcd. forC₁₈H₁₅F₃N₄O, 360.1; m/z found, 361.0 [M+H]⁺.

Example 108:1-(2-Cyclopropyl-2,2-difluoro-ethyl)-6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridine

The title compound was prepared in a manner analogous to Example 98using1-cyclopropyl-2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]ethenone(Example 76) instead of1-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]butan-2-one.MS (ESI): mass calcd. for C₁₈H₁₄F₅N₃, 367.1; m/z found, 368.2 [M+H]⁺. ¹HNMR (500 MHz, DMSO-d₆) δ 8.91 (d, J=1.9 Hz, 1H), 8.59-8.55 (m, 1H), 8.42(d, J=0.9 Hz, 1H), 8.10-8.03 (m, 2H), 7.62-7.53 (m, 1H), 7.30 (t, J=54.1Hz, 1H), 5.14 (t, J=13.3 Hz, 2H), 1.52-1.39 (m, 1H), 0.54-0.47 (m, 2H),0.47-0.41 (m, 2H).

Example 109:1-(2-Cyclopropyl-2,2-difluoro-ethyl)-6-[3-(difluoromethoxy)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridine

A mixture of1-cyclopropyl-2-[6-[3-(difluoromethoxy)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]ethenone(Example 77,150 mg, 0.415 mmol) and Deoxo-Fluor® (50% in THF, 1.8 mL,4.07 mmol, 2.26 M) was stirred at room temperature for 24 h, then at 80°C. for 2 h. The reaction was quenched with saturated sodium bicarbonate(11 mL) at 0° C. The layers were separated and the aqueous layer wasextracted with EtOAc (3×5 mL). The combined organics were dried overMgSO₄, filtered and evaporated. The residue was purified by preparativeHPLC (METHOD G) to afford the title compound (38 mg, 0.099 mmol, 24%) asa brown oil. MS (ESI): mass calcd. for C₁₈H₁₄F₅N₃O, 383.1; m/z found,384.2 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 8.91 (d, J=2.0 Hz, 1H),8.56-8.52 (m, 1H), 8.42 (d, J=1.0 Hz, 1H), 7.84 (dd, J=7.6, 2.3 Hz, 1H),7.80-7.73 (m, 1H), 7.61 (dd, J=10.5, 8.6 Hz, 1H), 7.38 (t, J=73.2 Hz,1H), 5.13 (t, J=13.3 Hz, 2H), 1.52-1.38 (m, 1H), 0.54-0.46 (m, 2H),0.47-0.40 (m, 2H).

Example 110:6-[3-(Difluoromethyl)-4-fluoro-phenyl]-1-[(3-methyloxetan-3-yl)methyl]pyrazolo[4,3-b]pyridine

The title compound was prepared in a manner analogous to Intermediate16, Step A, using6-(3-(difluoromethyl)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 3) instead of 6-bromo-1H-pyrazolo[4,3-B]pyridine, and3-(bromomethyl)-3-methyloxetane instead of (chloromethyl)(ethyl)sulfane,and THE instead of DMF. MS (ESI): mass calcd. for C₁₈H₁₆F₃N₃O, 347.1;m/z found, 348.0 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.80 (d, J=2.0 Hz,1H), 8.21 (d, J=0.9 Hz, 1H), 8.14 (dd, J=2.1, 0.9 Hz, 1H), 7.89-7.85 (m,1H), 7.77-7.72 (m, 1H), 7.32-7.25 (m, 1H), 6.97 (t, J=54.9 Hz, 1H), 4.83(d, J=6.2 Hz, 2H), 4.70 (s, 2H), 4.47 (d, J=6.2 Hz, 2H), 1.29 (s, 3H).

Example 111:(RS)-1-(Tetrahydrofuran-2-ylmethyl)-6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridinehydrochloride Salt

The title compound was prepared in a manner analogous to Intermediate16, Step A, using6-(3-(trifluoromethyl)phenyl)-1H-pyrazolo[4,3-b]pyridine (Intermediate8) instead of 6-bromo-1H-pyrazolo[4,3-b]pyridine, and2-(chloromethyl)tetrahydrofuran instead of chloromethyl)(ethyl)sulfane.Heating was not required, and the hydrochloride salt was obtained upontreatment from 3N HCl in MeOH after purification by reversed phase HPLC(METHOD H). MS (ESI): mass calcd. for C₁₈H₁₆F₃N₃O, 347.1; m/z found,348.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.95 (d, J=1.85 Hz, 1H), 8.63(dd, J=1.85, 0.92 Hz, 1H), 8.37 (d, J=0.92 Hz, 1H), 8.23-8.04 (m, 2H),7.93-7.70 (m, 2H), 4.73-4.51 (m, 2H), 4.41-4.16 (m, 1H), 3.70-3.64 (m,1H), 3.61-3.51 (m, 1H), 2.07-1.90 (m, 1H), 1.86-1.53 (m, 3H).

Example 112:(RS)-6-[3-(Difluoromethoxy)-4-fluoro-phenyl]-1-(tetrahydrofuran-2-ylmethyl)pyrazolo[4,3-b]pyridine

The title compound was prepared in a manner analogous to Example 18using 6-(3-(difluoromethoxy)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 4) instead of6-[3-(difluoromethyl)-4-fluoro-phenyl]-1H-pyrazolo[4,3-b]pyridine. MS(ESI): mass calcd. for C₁₈H₁₆F₃N₃O₂, 363.1; m/z found, 364.1 [M+H]⁺. ¹HNMR (500 MHz, DMSO-d₆) δ 8.86 (d, J=2.0 Hz, 1H), 8.46 (dd, J=2.0, 1.0Hz, 1H), 8.33 (d, J=0.9 Hz, 1H), 7.84 (dd, J=7.6, 2.3 Hz, 1H), 7.80-7.75(m, 1H), 7.59 (dd, J=10.5, 8.6 Hz, 1H), 7.39 (t, J=73.2 Hz, 1H), 4.57(d, J=5.6 Hz, 2H), 4.32-4.26 (m, 1H), 3.71-3.64 (m, 1H), 3.62-3.55 (m,1H), 2.00-1.91 (m, 1H), 1.83-1.62 (m, 3H).

Example 113:(RS)-6-[3-(Difluoromethyl)-4-fluoro-phenyl]-1-(tetrahydrofuran-3-ylmethyl)pyrazolo[4,3-b]pyridine

The title compound was prepared in a manner analogous to Intermediate16, Step A, using6-(3-(difluoromethyl)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 3) instead of 6-bromo-1H-pyrazolo[4,3-b]pyridine, and3-(bromomethyl)tetrahydrofuran instead of (chloromethyl)(ethyl)sulfane.Purified by prep HPLC (METHOD D). MS (ESI): mass calcd. for C₁₈H₁₆F₃N₃O,347.1; m/z found, 348.1 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.78 (d, J=1.9Hz, 1H), 8.29 (d, J=1.0 Hz, 1H), 7.93-7.81 (m, 2H), 7.81-7.70 (m, 1H),7.30 (ddt, J=9.7, 8.5, 1.1 Hz, 1H), 6.99 (t, J=54.8 Hz, 1H), 4.41 (d,J=7.7 Hz, 2H), 3.99 (td, J=8.3, 5.4 Hz, 1H), 3.84-3.73 (m, 2H), 3.65(dd, J=9.0, 4.7 Hz, 1H), 3.01 (ddt, J=11.6, 7.9, 3.9 Hz, 1H), 2.07 (dtd,J=13.3, 8.1, 5.4 Hz, 1H), 1.82-1.68 (m, 1H).

Example 114:(RS)-5-((6-(3-(Difluoromethoxy)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)methyl)-1-methylpyrrolidin-2-one

The title compound was prepared in a manner analogous to Intermediate16, Step A, using6-(3-(difluoromethoxy)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 4) instead of 6-bromo-1H-pyrazolo[4,3-b]pyridine, and5-(bromomethyl)-1-methylpyrrolidin-2-one instead of(chloromethyl)(ethyl)sulfane. MS (ESI): mass calcd. for C₁₉H₁₇F₃N₄O₂,390.1; m/z found, 391.1 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 8.89 (d,J=1.9 Hz, 1H), 8.60-8.50 (m, 1H), 8.44-8.33 (m, 1H), 7.91-7.83 (m, 1H),7.82-7.75 (m, 1H), 7.65-7.57 (m, 1H), 7.38 (t, J=73.2 Hz, 1H), 4.75 (dd,J=14.6, 4.6 Hz, 1H), 4.68 (dd, J=14.6, 5.2 Hz, 1H), 4.14-4.02 (m, 1H),2.71 (s, 3H), 2.08-1.92 (m, 2H), 1.83-1.67 (m, 2H).

Example 115:(RS)-5-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-1-methyl-pyrrolidin-2-one

The title compound was prepared in a manner analogous to Intermediate16, Step A, using6-(3-(difluoromethyl)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 3) instead of 6-bromo-1H-pyrazolo[4,3-b]pyridine, and5-(bromomethyl)-1-methylpyrrolidin-2-one instead of(chloromethyl)(ethyl)sulfane. MS (ESI): mass calcd. for C₁₉H₁₇F₃N₄O,374.1; m/z found, 375.1 [M+H]⁺. ¹H NMR (500 MHz, MeOD) δ 8.80 (d, J=1.8Hz, 1H), 8.39 (dd, J=1.9, 1.0 Hz, 1H), 8.27 (d, J=1.0 Hz, 1H), 8.00(ddd, J=7.5, 2.2, 1.1 Hz, 1H), 7.95 (dddd, J=8.3, 3.4, 2.2, 0.9 Hz, 1H),7.41 (dd, J=9.9, 8.7 Hz, 1H), 7.08 (t, J=54.6 Hz, 1H), 4.83-4.66 (m,2H), 4.35-4.07 (m, 1H), 2.85 (s, 3H), 2.34-2.05 (m, 2H), 1.95 (ddt,J=12.1, 8.9, 2.9 Hz, 1H), 1.86-1.68 (m, 1H).

Example 116:(RS)-3-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-1-methyl-pyrrolidin-2-one

The title compound was prepared in a manner analogous to Intermediate16, Step A, using6-(3-(difluoromethyl)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 3) instead of 6-bromo-1H-pyrazolo[4,3-b]pyridine, and3-(bromomethyl)-1-methylpyrrolidin-2-one instead of(chloromethyl)(ethyl)sulfane. MS (ESI): mass calcd. for C₁₉H₁₇F₃N₄O,374.1; m/z found, 375.1 [M+H]⁺. ¹H NMR (500 MHz, MeOD) δ 8.81 (d, J=1.9Hz, 1H), 8.44 (dd, J=1.9, 1.0 Hz, 1H), 8.26 (d, J=1.0 Hz, 1H), 8.07-7.94(m, 2H), 7.50-7.40 (m, 1H), 7.11 (t, J=54.6 Hz, 1H), 4.82-4.76 (m, 2H),3.39-3.28 (m, 1H), 3.20-3.04 (m, 2H), 2.75 (d, J=0.8 Hz, 3H), 2.20(dddd, J=13.2, 9.3, 8.2, 4.0 Hz, 1H), 2.02 (dddd, J=13.1, 8.9, 7.9, 7.0Hz, 1H).

Example 117:(S)-3-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-1-methyl-pyrrolidin-2-one

The title compound was prepared by the separation of Example 116 usingchiral SFC (Stationary phase: Chiralpak IC, 5 um 250×21 mm, Mobilephase: 30% methanol, 70% CO₂). MS (ESI): mass calcd. for C₁₉H₁₇F₃N₄O,374.1; m/z found, 375.1 [M+H]⁺.

Example 118:(R)-3-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-1-methyl-pyrrolidin-2-one

The title compound was prepared by the separation of Example 116 usingchiral SFC (Stationary phase: Chiralpak IC, 5 M 250×21 mm, Mobile phase:30% methanol, 70% CO₂). MS (ESI): mass calcd. for C₁₉H₁₇F₃N₄O, 374.1;m/z found, 375.1 [M+H]⁺.

Example 119: (RS)3-((6-(3-(Difluoromethoxy)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)methyl)-1-methylpyrrolidin-2-one

The title compound was prepared in a manner analogous to Example 19using 3-(bromomethyl)-1-methylpyrrolidin-2-one instead of4-(chloromethyl)-1-methyl-pyrrolidin-2-one. MS (ESI): mass calcd. forC₁₉H₁₇F₃N₄O₂, 390.4; m/z found, 391.1 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆)δ 8.87 (d, J=2.0 Hz, 1H), 8.52-8.49 (m, 1H), 8.35 (d, J=1.0 Hz, 1H),7.86 (dd, J=7.6, 2.3 Hz, 1H), 7.82-7.75 (m, 1H), 7.60 (dd, J=10.5, 8.6Hz, 1H), 7.38 (t, J=73.2 Hz, 1H), 4.74-4.65 (m, 2H), 3.23-3.16 (m, 1H),3.07-2.99 (m, 2H), 2.66 (s, 3H), 1.98-1.90 (m, 1H), 1.81-1.71 (m, 1H).

Example 120:(RS)-4-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-1-methyl-pyrrolidin-2-one

The title compound was prepared in a manner analogous to Intermediate16, Step A, using6-(3-(difluoromethyl)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 3) instead of 6-bromo-1H-pyrazolo[4,3-b]pyridine, and4-(bromomethyl)-1-methyl-2-pyrrolidinone instead of(chloromethyl)(ethyl)sulfane. MS (ESI): mass calcd. for C₁₉H₁₇F₃N₄O,374.1; m/z found, 375.1 [M+H]⁺. ¹H NMR (500 MHz, MeOD) δ 8.81 (d, J=1.9Hz, 1H), 8.44 (dd, J=1.8, 1.0 Hz, 1H), 8.25 (d, J=1.0 Hz, 1H), 8.08-7.93(m, 2H), 7.42 (tt, J=9.7, 1.0 Hz, 1H), 7.08 (t, J=54.6 Hz, 1H),4.68-4.51 (m, 2H), 3.52 (dd, J=10.3, 8.1 Hz, 1H), 3.38 (dd, J=10.3, 5.4Hz, 1H), 3.19-3.06 (m, 1H), 2.84-2.73 (m, 3H), 2.53 (dd, J=17.0, 8.9 Hz,1H), 2.31 (dd, J=17.0, 6.3 Hz, 1H).

Example 121:(S)-4-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-1-methyl-pyrrolidin-2-one

The title compound was prepared by the separation of Example 120 usingchiral SFC (Stationary phase: CHIRALPAK AD-H 5 μm 250*30 mm, Mobilephase: 75% CO₂, 25% MeOH). MS (ESI): mass calcd. for C₁₉H₁₇F₃N₄O, 374.1;m/z found, 375.0 [M+H]⁺.

Example 122:(R)-4-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-1-methyl-pyrrolidin-2-one

The title compound was prepared by the separation of Example 120 usingchiral SFC (Stationary phase: CHIRALPAK AD-H 5 μm 250*30 mm, Mobilephase: 75% CO₂, 25% MeOH). MS (ESI): mass calcd. for C₁₉H₁₇F₃N₄O, 374.1;m/z found, 375.0 [M+H]⁺.

Example 123:(R,S)-4-((6-(3-(difluoromethoxy)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)methyl)-3-methyloxazolidin-2-one

The title compound was prepared in a manner analogous to Example 18using 6-(3-(difluoromethoxy)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 4) instead of6-[3-(difluoromethyl)-4-fluoro-phenyl]-1H-pyrazolo[4,3-b]pyridine, and(RS)-4-(chloromethyl)-3-methyloxazolidin-2-one (Intermediate 20) insteadof 2-(chloromethyl)oxolane. MS (ESI): mass calcd. for C₁₈H₁₅F₃N₄O₃,392.1; m/z found, 393.1 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 8.90 (d,J=1.9 Hz, 1H), 8.62-8.58 (m, 1H), 8.42-8.39 (m, 1H), 7.87 (dd, J=7.6,2.3 Hz, 1H), 7.82-7.77 (m, 1H), 7.61 (dd, J=10.5, 8.6 Hz, 1H), 7.38 (t,J=73.2 Hz, 1H), 4.83 (dd, J=14.8, 4.1 Hz, 1H), 4.73 (dd, J=14.7, 4.6 Hz,1H), 4.39-4.28 (m, 2H), 4.13 (dd, J=8.0, 4.0 Hz, 1H), 2.75 (s, 3H).

Example 124:(RS)-4-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-3-methyl-oxazolidin-2-one

The title compound was prepared in a manner analogous to Intermediate16, Step A, using6-(3-(difluoromethyl)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 3) instead of 6-bromo-1H-pyrazolo[4,3-b]pyridine, and(RS)-4-(chloromethyl)-3-methyloxazolidin-2-one (Intermediate 20) insteadof (chloromethyl)(ethyl)sulfane. MS (ESI): mass calcd. for C₁₈H₁₅F₃N₄O₂,376.1; m/z found, 377.1 [M+H]⁺. ¹H NMR (500 MHz, MeOD) δ 8.82 (d, J=1.9Hz, 1H), 8.44 (dd, J=1.9, 1.0 Hz, 1H), 8.28 (d, J=1.0 Hz, 1H), 8.07-7.99(m, 1H), 7.99-7.93 (m, 1H), 7.42 (dd, J=9.9, 8.7 Hz, 1H), 7.08 (t,J=54.6 Hz, 1H), 4.86-4.80 (m, 1H), 4.77-4.69 (m, 1H), 4.47-4.33 (m, 2H),4.33-4.23 (m, 1H), 2.87 (s, 3H).

Example 125:(RS)-5-[[6-[3-(Difluoromethoxy)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]oxazolidin-2-one

The title compound was prepared in a manner analogous to Example 20,using 6-(3-(difluoromethoxy)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 4) instead of6-(3-(difluoromethyl)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridine. MS(ESI): mass calcd. for C₁₇H₁₃F₃N₄O₃, 378.1; m/z found, 379.1 [M+H]⁺. ¹HNMR (500 MHz, DMSO-d₆) δ 8.88 (d, J=1.9 Hz, 1H), 8.52-8.48 (m, 1H), 8.39(d, J=0.9 Hz, 1H), 7.85 (dd, J=7.6, 2.3 Hz, 1H), 7.80-7.75 (m, 1H), 7.61(dd, J=10.5, 8.6 Hz, 1H), 7.52-7.48 (m, 1H), 7.38 (t, J=73.2 Hz, 1H),5.08-5.00 (m, 1H), 4.83 (dd, J=15.0, 6.2 Hz, 1H), 4.77 (dd, J=14.9, 4.6Hz, 1H), 3.66-3.60 (m, 1H), 3.38-3.33 (m, 1H).

Example 126:(RS)-5-[[6-[4-Chloro-3-(difluoromethoxy)phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]oxazolidin-2-one

The title compound was prepared in a manner analogous to Example 20,using 6-(4-chloro-3-(difluoromethoxy)phenyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 5) instead of6-(3-(difluoromethyl)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridine. MS(ESI): mass calcd. for C₁₇H₁₃CF₂N₄O₃, 394.1; m/z found, 395.1 [M+H]⁺. ¹HNMR (300 MHz, DMSO-d₆) δ 8.91 (d, J=1.9 Hz, 1H), 8.58-8.49 (m, 1H),8.43-8.36 (m, 1H), 7.87-7.72 (m, 3H), 7.55-7.47 (m, 1H), 7.44 (t, J=73.2Hz, 1H), 5.12-4.97 (m, 1H), 4.90-4.73 (m, 2H), 3.63 (t, J=9.0 Hz, 1H),3.42-3.30 (m, 1H).

Example 127:(RS)-5-[[6-[3-(1,1-Difluoroethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]oxazolidin-2-one

The title compound was prepared in a manner analogous to Example 20,using6-(3-(1,1-difluoroethyl)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 6) instead of6-(3-(difluoromethyl)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridine. MS(ESI): mass calcd. for C₁₈H₁₅F₃N₄O₂, 376.1; m/z found, 377.1 [M+H]⁺. ¹HNMR (500 MHz, DMSO-d₆) δ 8.88 (d, J=1.9 Hz, 1H), 8.53-8.50 (m, 1H), 8.39(d, J=1.0 Hz, 1H), 8.05-7.99 (m, 1H), 7.99-7.95 (m, 1H), 7.56 (dd,J=11.0, 8.6 Hz, 1H), 7.52-7.47 (m, 1H), 5.08-5.00 (m, 1H), 4.84 (dd,J=14.9, 6.2 Hz, 1H), 4.79 (dd, J=14.9, 4.4 Hz, 1H), 3.66-3.60 (m, 1H),3.38-3.33 (m, 1H), 2.10 (t, J=19.1 Hz, 3H).

Example 128:(RS)-5-((6-(3-(Difluoromethoxy)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)methyl)-3-methyloxazolidin-2-one

The title compound was prepared in a manner analogous to Intermediate16, Step A, using6-(3-(difluoromethoxy)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 4) instead of 6-bromo-1H-pyrazolo[4,3-B]pyridine, and5-(chloromethyl)-3-methyloxazolidin-2-one instead of(chloromethyl)(ethyl)sulfane. MS (ESI): mass calcd. for C₁₈H₁₅F₃N₄O₃,392.1; m/z found, 393.1 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 8.89 (d,J=1.9 Hz, 1H), 8.55-8.46 (m, 1H), 8.43-8.35 (m, 1H), 7.90-7.82 (m, 1H),7.81-7.72 (m, 1H), 7.61 (dd, J=10.4, 8.7 Hz, 1H), 7.37 (t, J=73.1 Hz,1H), 5.03-4.92 (m, 1H), 4.90-4.73 (m, 2H), 3.76-3.65 (m, 1H), 3.43 (dd,J=9.0, 5.9 Hz, 1H), 2.67 (s, 3H).

Example 129:(5R)-5-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-3-methyl-oxazolidin-2-one

The title compound was prepared in a manner analogous to Intermediate16, Step A, using6-(3-(difluoromethyl)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 3) instead of 6-bromo-1H-pyrazolo[4,3-b]pyridine, and(R)-5-(chloromethyl)-3-methyloxazolidin-2-one (Intermediate 18) insteadof (chloromethyl)(ethyl)sulfane. MS (ESI): mass calcd. for C₁₈H₁₅F₃N₄O₂,376.1; m/z found, 377.1 [M+H]⁺. ¹H NMR (500 MHz, MeOD) δ 8.79 (d, J=1.9Hz, 1H), 8.38 (dd, J=1.9, 1.0 Hz, 1H), 8.27 (d, J=1.0 Hz, 1H), 8.06-7.93(m, 2H), 7.41 (dd, J=9.9, 8.7 Hz, 1H), 7.07 (t, J=54.6 Hz, 1H), 5.04(dtd, J=9.1, 5.6, 3.4 Hz, 1H), 4.92-4.75 (m, 2H), 3.78 (t, J=9.1 Hz,1H), 3.61 (dd, J=9.2, 5.6 Hz, 1H), 2.70 (s, 3H).

Example 130:(5S)-5-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-3-methyl-oxazolidin-2-one

The title compound was prepared in a manner analogous to Intermediate16, Step A, using6-(3-(difluoromethyl)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 3) instead of 6-bromo-1H-pyrazolo[4,3-b]pyridine, and(S)-5-(chloromethyl)-3-methyloxazolidin-2-one (Intermediate 19) insteadof (chloromethyl)(ethyl)sulfane. MS (ESI): mass calcd. for C₁₈H₁₅F₃N₄O₂,376.1; m/z found, 377.1 [M+H]⁺. ¹H NMR (500 MHz, MeOD) δ 8.76 (dd,J=1.7, 0.9 Hz, 1H), 8.35 (dt, J=1.8, 0.8 Hz, 1H), 8.29-8.22 (m, 1H),7.97 (dd, J=7.0, 2.1 Hz, 1H), 7.92 (d, J=6.3 Hz, 1H), 7.37 (t, J=9.5 Hz,1H), 7.06 (t, J=54.6 Hz, 1H), 5.02 (dtd, J=9.2, 5.7, 3.5 Hz, 1H),4.87-4.74 (m, 2H), 3.77 (t, J=9.1 Hz, 1H), 3.59 (dd, J=9.2, 5.7 Hz, 1H),2.70 (s, 3H).

Example 131:(RS)-5-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-3-ethyl-oxazolidin-2-one

The title compound was prepared in a manner analogous to Intermediate16, Step A, using6-(3-(difluoromethyl)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 3) instead of 6-bromo-1H-pyrazolo[4,3-b]pyridine, and5-(bromomethyl)-3-ethyl-1,3-oxazolidin-2-one instead of(chloromethyl)(ethyl)sulfane. MS (ESI): mass calcd. for C₁₉H₁₇F₃N₄O₂,390.1; m/z found, 391.2 [M+H]⁺. ¹H NMR (500 MHz, MeOD) δ 8.79 (d, J=1.9Hz, 1H), 8.38 (dd, J=1.9, 1.0 Hz, 1H), 8.27 (d, J=1.0 Hz, 1H), 8.05-7.93(m, 2H), 7.41 (dd, J=10.0, 8.7 Hz, 1H), 7.07 (t, J=54.6 Hz, 1H), 5.06(dtd, J=9.0, 5.2, 3.1 Hz, 1H), 4.94-4.87 (m, 1H), 4.82-4.74 (m, 1H),3.77 (t, J=9.2 Hz, 1H), 3.63 (dd, J=9.2, 5.3 Hz, 1H), 3.17-3.00 (m, 2H),0.90 (t, J=7.3 Hz, 3H).

Example 132:(S)-5-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-3-ethyl-oxazolidin-2-one

The title compound was prepared by the separation of Example 131 usingchiral SFC (Stationary phase: Chiralpak IA, Sum 250×21 mm, Mobile phase:35% methanol with 0.2% triethylamine, 65% CO₂). MS (ESI): mass calcd.for C₁₉H₁₇F₃N₄O₂, 390.1; m/z found, 391.2 [M+H]⁺.

Example 133:(R)-5-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-3-ethyl-oxazolidin-2-one

The title compound was prepared by the separation of Example 131 usingchiral SFC (Stationary phase: Chiralpak IA, Sum 250×21 mm, Mobile phase:35% methanol with 0.2% triethylamine, 65% CO₂). MS (ESI): mass calcd.for C₁₉H₁₇F₃N₄O₂, 390.1; m/z found, 391.2 [M+H]⁺.

Example 134:(RS)-3-Cyclopropyl-5-[[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]oxazolidin-2-one

The title compound was prepared in a manner analogous to Intermediate16, Step A, using6-(3-(difluoromethyl)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 3) instead of 6-bromo-1H-pyrazolo[4,3-b]pyridine, and5-(bromomethyl)-3-cyclopropyl-1,3-oxazolidin-2-one instead of(chloromethyl)(ethyl)sulfane. MS (ESI): mass calcd. for C₂H₁₇F₃N₄O₂,402.1; m/z found, 403.2 [M+H]⁺. ¹H NMR (500 MHz, MeOD) δ 8.79 (d, J=1.9Hz, 1H), 8.35 (dd, J=1.9, 1.0 Hz, 1H), 8.27 (d, J=1.0 Hz, 1H), 8.05-7.94(m, 2H), 7.45-7.37 (m, 1H), 7.07 (t, J=54.6 Hz, 1H), 5.01 (dtd, J=9.2,4.7, 3.0 Hz, 1H), 4.93-4.86 (m, 1H), 4.80-4.63 (m, 1H), 3.78 (t, J=9.1Hz, 1H), 3.58 (dd, J=9.2, 4.7 Hz, 1H), 2.29 (tt, J=7.0, 3.6 Hz, 1H),0.66-0.51 (m, 2H), 0.35 (dtd, J=11.1, 3.7, 2.1 Hz, 1H), 0.16 (dtd,J=10.2, 3.6, 2.0 Hz, 1H).

Example 135:(S)-3-Cyclopropyl-5-[[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]oxazolidin-2-one

The title compound was prepared by the separation of Example 134 usingchiral SFC (Stationary phase: Chiralpak AS, Sum 250×21 mm, Mobile phase:15% methanol:isopropanol (1:1) with 0.2% isopropylamine, 85% CO₂). MS(ESI): mass calcd. for C₂H₁₇F₃N₄O₂, 402.1; m/z found, 403.2 [M+H]⁺.

Example 136:(R)-3-Cyclopropyl-5-[[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]oxazolidin-2-one

The title compound was prepared by the separation of Example 134 usingchiral SFC (Stationary phase: Chiralpak AS, 5 um 250×21 mm, Mobilephase: 15% methanol:isopropanol (1:1) with 0.2% isopropylamine, 85%CO₂). MS (ESI): mass calcd. for C₂H₁₇F₃N₄O₂, 402.1; m/z found, 403.2[M+H]⁺.

Example 137:2-[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1-(2-thienyl)ethanone

The title compound was prepared in a manner analogous to Intermediate16, Step A, using 2-chloro-1-(thiophen-2-yl)ethan-1-one instead of(chloromethyl)(ethyl)sulfane, and6-(3-(difluoromethyl)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 3) instead of 6-bromo-1H-pyrazolo[4,3-b]pyridine. MS(ESI): mass calcd. for C₁₉H₁₂F₃N₃OS, 387.1; m/z found, 388.1 [M+H]⁺. ¹HNMR (300 MHz, DMSO-d₆) δ 8.92 (d, J=1.9 Hz, 1H), 8.59-8.52 (m, 1H),8.46-8.37 (m, 1H), 8.30-8.22 (m, 1H), 8.18-8.12 (m, 1H), 8.10-8.01 (m,2H), 7.61-7.50 (m, 1H), 7.41-7.35 (m, 1H), 7.28 (t, J=54.2 Hz, 1H), 6.20(s, 2H).

Example 138:2-[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1-(3-thienyl)ethanone

The title compound was prepared in a manner analogous to Intermediate16, Step A, using 2-chloro-1-(thiophen-3-yl)ethan-1-one instead of(chloromethyl)(ethyl)sulfane, and6-(3-(difluoromethyl)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 3) instead of 6-bromo-1H-pyrazolo[4,3-b]pyridine. MS(ESI): mass calcd. for C₁₉H₁₂F₃N₃OS, 387.1; m/z found, 388.0 [M+H]⁺. ¹HNMR (500 MHz, DMSO-d₆) δ 8.91 (d, J=1.9 Hz, 1H), 8.76 (dd, J=2.9, 1.3Hz, 1H), 8.56-8.52 (m, 1H), 8.41 (d, J=1.0 Hz, 1H), 8.09-8.01 (m, 2H),7.74 (dd, J=5.0, 2.8 Hz, 1H), 7.60 (dd, J=5.1, 1.3 Hz, 1H), 7.58-7.51(m, 1H), 7.28 (t, J=54.1 Hz, 1H), 6.15 (s, 2H).

Example 139:2-[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1-(4-pyridyl)ethanone

The title compound was prepared in a manner analogous to Example 14using 2-bromo-1-(pyridin-4-yl)ethan-1-one (Intermediate 22) instead of2-bromo-1-(2-pyridyl)ethanone hydrobromide. MS (ESI): mass calcd. forC₂₀H₁₃F₃N₄O, 382.1; m/z found, 383.1 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ8.97-8.85 (m, 3H), 8.57-8.51 (m, 1H), 8.46-8.40 (m, 1H), 8.09-8.00 (m,2H), 7.99-7.94 (m, 2H), 7.59-7.51 (m, 1H), 7.28 (t, J=54.1 Hz, 1H), 6.32(s, 2H).

Example 140:2-(6-(3-(Difluoromethyl)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)-1-(3-fluoropyridin-2-yl)ethan-1-one

The title compound was prepared in a manner analogous to Example 15using 2-bromo-1-(3-fluoropyridin-2-yl)ethan-1-one (Intermediate 24)instead of 2-bromo-1-(5-fluoropyridin-2-yl)ethan-1-one. MS (ESI): masscalcd. for C₂₀H₁₂F₄N₄O, 400.1; m/z found, 401.1 [M+H]⁺. ¹H NMR (500 MHz,DMSO-d₆) δ 8.99-8.86 (m, 1H), 8.74-8.65 (m, 1H), 8.61-8.53 (m, 1H),8.46-8.38 (m, 1H), 8.05 (d, J=6.2 Hz, 2H), 8.02-7.94 (m, 1H), 7.92-7.83(m, 1H), 7.60-7.49 (m, 1H), 7.28 (t, J=54.1 Hz, 1H), 6.25 (s, 2H).

Example 141:2-(6-(3-(Difluoromethyl)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)-1-(3,5-difluoropyridin-2-yl)ethan-1-one

The title compound was prepared in a manner analogous to Example 15using 2-bromo-1-(3,5-difluoropyridin-2-yl)ethan-1-one (Intermediate 23)instead of 2-bromo-1-(5-fluoropyridin-2-yl)ethan-1-one. MS (ESI): masscalcd. for C₂₀H₁₁F₅N₄O, 418.1; m/z found, 419.1 [M+H]⁺. ¹H NMR (500 MHz,DMSO-d₆) δ 8.91 (d, J=2.0 Hz, 1H), 8.80 (d, J=2.3 Hz, 1H), 8.56-8.51 (m,1H), 8.43-8.41 (m, 1H), 8.24-8.18 (m, 1H), 8.08-8.02 (m, 2H), 7.60-7.52(m, 1H), 7.28 (t, J=54.2 Hz, 1H), 6.22 (s, 2H).

Example 142:2-(6-(3-(Difluoromethyl)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)-1-(pyrazin-2-yl)ethan-1-one

The title compound was prepared in a manner analogous to Example 15using 2-bromo-1-(pyrazin-2-yl)ethan-1-one (Intermediate 25) instead of2-bromo-1-(5-fluoropyridin-2-yl)ethan-1-one. MS (ESI): mass calcd. forC₂₀H₁₁F₅N₄O, 383.1; m/z found, 384.1 [M+H]⁺. ¹H NMR (500 MHz,Methanol-d4) δ 9.20 (d, J=1.5 Hz, 1H), 8.91-8.89 (m, 1H), 8.85 (d, J=1.9Hz, 1H), 8.84-8.82 (m, 1H), 8.38-8.36 (m, 1H), 8.34-8.31 (m, 1H),7.97-7.91 (m, 2H), 7.42-7.37 (m, 1H), 7.06 (t, J=54.6 Hz, 1H), 6.31 (s,2H). NMR in MeOH results in mixture of ketone and methanol hemiacetal

BIOLOGICAL ASSAYS

Effects of Test Articles on Cloned Human NR1/GluN2B Ion ChannelsExpressed in Mammalian Cells

NMDA receptors are ion channels that are highly permeable to Ca²⁺ ions,rendering it possible to monitor NMDA receptor function using cell-basedcalcium flux assay. In this assay, co-agonists glutamate and glycine areadded to cells heterologously expressing human GluN1/GluN2B NMDAreceptors to initiate cellular Ca²⁺ influx. The time course of thechanges in intracellular calcium is measured using a fluorescent dye anda FLIPR (Fluorometric Imaging Plate Reader) device.

Twenty four hours before measurements, the expression of the NMDAreceptors in the stable cell line is induced with Tet-On induciblesystem in the presence of a non-selective NMDA receptor blocker. On theday of the experiment, cell culture media is carefully washed and thecells are loaded with Calcium 5 Dye Kit (Molecular Devices) in dyeloading buffer containing 137 mM NaCl, 4 mM KCl, 2 mM CaCl₂, 0.5 mMMgCl₂ (standard assay) or 1.5 mM MgCl₂ (HTS assay), 10 mM HEPES and 5 mMD-glucose; pH 7.4. After 1 h incubation at the room temperature, the dyeis washed away with the assay buffer (137 mM NaCl (standard assay) or150 mM (HTS assay), 4 mM KCl (standard assay) or 3 mM (HTS assay), 2 mMCaC₂, 0.01 mM EDTA, 10 mM HEPES and 5 mM D-glucose; pH 7.4) In the FLIPRTETRA reader, various concentrations of the test compounds are added tothe cells for 5 min while fluorescence is monitored to detect potentialagonist activity. Next, co-agonists, glutamate and glycine are added foranother 5 minutes. The concentration of glutamate corresponding to ˜EC₄₀(standard assay) or EC₄₀ (HTS assay) is used to maximize the assay'ssignal window and ability to detect NMDA receptor antagonists andnegative allosteric modulators. A saturating concentration (10 μM) ofglycine is also present in the assay. A non-selective NMDA receptorantagonist, (+)MK-801 is used as a positive control for antagonistactivity. The fluorescent signal in the presence of test compounds isquantified and normalized to the signal defined by the appropriatecontrol wells.

TABLE 3 GluN2B Standard Assay Ex # Compound Name IC₅₀ (μM) 11-[6-(3,5-Difluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]butan- 0.019 2-one;2 3-Methyl-1-[6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3- 0.061b]pyridin-1-yl]butan-2-one; 3 (RS)-3-Methyl-1-[6-[3- 0.567(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]butan- 2-ol; 41-[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3- 0.010b]pyridin-1-yl]butan-2-one; 5 (RS)-1-[6-[3-(Difluoromethyl)-4-fluoro-0.048 phenyl]pyrazolo[4,3-b]pyridin-1-yl]butan-2-ol; 6(E/Z)-3-Methyl-1-[6-[3- 2.480(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]butan- 2-one oxime;7 1-[6-(4-Fluoro-3-methyl-phenyl)pyrazolo[4,3-b]pyridin-1- 0.021yl]-3-methyl-butan-2-one; 8(RS)-1-[6-(4-Fluoro-3-methyl-phenyl)pyrazolo[4,3- 0.222b]pyridin-1-yl]-3-methyl-butan-2-ol; 91-Cyclopropyl-2-[6-(3,4,5-trifluorophenyl)pyrazolo[4,3- 0.030b]pyridin-1-yl]ethanone; 10 (RS)-1-Cyclopropyl-2-[6-(3,4,5- 0.696trifluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]ethanol; 11(RS)-1-(2-Cyclopropyl-2-methoxy-ethyl)-6-(3,4,5- 1.780trifluorophenyl)pyrazolo[4,3-b]pyridine; 12(RS)-6-[3-(Difluoromethoxy)-4-fluoro-phenyl]-1- 0.146(ethylsulfinylmethyl)pyrazolo[4,3-b]pyridine; 136-[3-(Difluoromethoxy)-4-fluoro-phenyl]-1- 1.800(ethylsulfonylmethyl)pyrazolo[4,3-b]pyridine; 142-[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3- 0.112b]pyridin-1-yl]-1-(2-pyridyl)ethanone; 152-(6-(3-(Difluoromethyl)-4-fluorophenyl)-1H-pyrazolo[4,3- 0.160b]pyridin-1-yl)-1-(5-fluoropyridin-2-yl)ethan-1-one; 162-(6-(3-(Difluoromethyl)-4-fluorophenyl)-1H-pyrazolo[4,3- 0.090b]pyridin-1-yl)-1-(pyridin-3-yl)ethan-1-one; 17(RS)-1-(Oxetan-2-ylmethyl)-6-[3- 0.085(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridine; 18(RS)-6-[3-(Difluoromethyl)-4-fluoro-phenyl]-1- 0.035(tetrahydrofuran-2-ylmethyl)pyrazolo[4,3-b]pyridine; 19(RS)-4-[[6-[3-(Difluoromethoxy)-4-fluoro- 0.992phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-1-methyl- pyrrolidin-2-one;20 (RS)-5[[6-[3-(Difluoromethyl)-4-fluoro- 0.197phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]oxazolidin-2- one; 21(S)-5-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3- 1.840b]pyridin-1-yl]methyl]oxazolidin-2-one; 22(R)-5-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3- 0.187b]pyridin-1-yl]methyl]oxazolidin-2-one; 231-[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3- 0.014b]pyridin-1-yl]propan-2-one; 241-[6-(4-Fluoro-3-methyl-phenyl)pyrazolo[4,3-b]pyridin-1- 0.015yl]propan-2-one; 251-[6-[3-(Difluoromethoxy)-4-fluoro-phenyl]pyrazolo[4,3- 0.034b]pyridin-1-yl]propan-2-one; 261-[6-[4-Chloro-3-(difluoromethoxy)phenyl]pyrazolo[4,3- 0.036b]pyridin-1-yl]propan-2-one; 271-[6-(5-Chloro-2-thienyl)pyrazolo[4,3-b]pyridin-1-yl]butan- 0.013 2-one;28 1-[6-(4-Fluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]butan-2- 0.032 one;29 1-[6-(3-Fluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]butan-2- 0.028 one;30 1-[6-[3-(Difluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1- 0.027yl]butan-2-one; 311-[6-[3-(1,1-Difluoroethyl)phenyl]pyrazolo[4,3-b]pyridin-1- 0.035yl]butan-2-one; 321-[6-(4-Fluoro-3-methyl-phenyl)pyrazolo[4,3-b]pyridin-1- 0.012yl]butan-2-one; 331-[6-(2,3-Difluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]butan- 0.046 2-one;34 1-[6-(3,4-Difluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]butan- 0.0172-one; 35 1-[6-(3,4-Difluorophenyl)-3-fluoro-pyrazolo[4,3-b]pyridin-0.005 1-yl]butan-2-one; 361-(6-(3-(Difluoromethyl)-4-fluorophenyl)-3-methyl-1H- 0.027pyrazolo[4,3-b]pyridin-1-yl)butan-2-one; 371-[6-[3-(1,1-Difluoroethyl)-4-fluoro-phenyl]pyrazolo[4,3- 0.041b]pyridin-1-yl]butan-2-one; 381-[6-[2-Fluoro-3-(trifluoromethyl)phenyl]pyrazolo[4,3- 0.030b]pyridin-1-yl]butan-2-one; 391-[6-[4-Fluoro-3-(trifluoromethyl)phenyl]pyrazolo[4,3- 0.075b]pyridin-1-yl]butan-2-one; 401-[6-[3-(Difluoromethoxy)-4-fluoro-phenyl]pyrazolo[4,3- 0.011b]pyridin-1-yl]butan-2-one; 411-[6-[4-Chloro-3-(difluoromethoxy)phenyl]pyrazolo[4,3- 0.021b]pyridin-1-yl]butan-2-one; 421-[6-(3,4,5-Trifluorophenyl)pyrazolo[4,3-b]pyridin-1- 0.027yl]butan-2-one; 43 1-[6-(2,3,4-Trifluorophenyl)pyrazolo[4,3-b]pyridin-1-0.028 yl]butan-2-one; 443-Methyl-1-(6-phenylpyrazolo[4,3-b]pyridin-1-yl)butan-2- 0.089 one; 451-[6-(4-Fluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]-3-methyl- 0.036butan-2-one; 461-[6-(3-Fluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]-3-methyl- 0.030butan-2-one; 47 1-[6-[3-(Difluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-0.023 yl]-3-methyl-butan-2-one; 481-[6-(2,3-Difluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]-3- 0.172methyl-butan-2-one; 491-[6-(3,4-Difluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]-3- 0.025methyl-butan-2-one; 501-[6-[2-Fluoro-3-(trifluoromethyl)phenyl]pyrazolo[4,3- 0.076b]pyridin-1-yl]-3-methyl-butan-2-one; 511-[6-[4-Fluoro-3-(trifluoromethyl)phenyl]pyrazolo[4,3- 0.296b]pyridin-1-yl]-3-methyl-butan-2-one; 521-[6-(4-Fluoro-2-methyl-phenyl)pyrazolo[4,3-b]pyridin-1- 0.090yl]-3-methyl-butan-2-one; 533-Methyl-1-[6-(3,4,5-trifluorophenyl)pyrazolo[4,3-b]pyridin- 0.0411-yl]butan-2-one; 543-Methyl-1-[6-(2,3,4-trifluorophenyl)pyrazolo[4,3-b]pyridin- 0.2051-yl]butan-2-one; 552-[6-(5-Chloro-2-thienyl)pyrazolo[4,3-b]pyridin-1-yl]-1- 0.008cyclopropyl-ethanone; 561-Cyclopropyl-2-[6-(5-methyl-2-thienyl)pyrazolo[4,3- 0.015b]pyridin-1-yl]ethanone; 571-Cyclopropyl-2-[6-(3-fluorophenyl)pyrazolo[4,3-b]pyridin- 0.0261-yl]ethanone; 581-Cyclopropyl-2-[6-(2-fluorophenyl)pyrazolo[4,3-b]pyridin- 0.1481-yl]ethanone; 591-Cyclopropyl-2-[6-(4-fluorophenyl)pyrazolo[4,3-b]pyridin- 0.0131-yl]ethanone; 60 1-Cyclopropyl-2-[6-(m-tolyl)pyrazolo[4,3-b]pyridin-1-0.008 yl]ethanone; 611-Cyclopropyl-2-[6-[3-(difluoromethyl)phenyl]pyrazolo[4,3- 0.012b]pyridin-1-yl]ethanone; 621-Cyclopropyl-2-[6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3- 0.046b]pyridin-1-yl]ethanone; 63 1-Cyclopropyl-2-[6-[3- 0.031(trifluoromethoxy)phenyl]pyrazolo[4,3-b]pyridin-1- yl]ethanone; 641-Cyclopropyl-2-[6-(2,3-difluorophenyl)pyrazolo[4,3- 0.037b]pyridin-1-yl]ethanone; 651-Cyclopropyl-2-[6-(3,4-difluorophenyl)pyrazolo[4,3- 0.013b]pyridin-1-yl]ethanone; 661-Cyclopropyl-2-[6-(3,5-difluorophenyl)pyrazolo[4,3- 0.019b]pyridin-1-yl]ethanone; 672-[6-(3-Chloro-2-fluoro-phenyl)pyrazolo[4,3-b]pyridin-1- 0.016yl]-1-cyclopropyl-ethanone; 682-[6-(3-Chloro-4-fluoro-phenyl)pyrazolo[4,3-b]pyridin-1- 0.007yl]-1-cyclopropyl-ethanone; 691-Cyclopropyl-2-[6-(4-fluoro-3-methyl-phenyl)pyrazolo[4,3- 0.019b]pyridin-1-yl]ethanone; 701-Cyclobutyl-246-(4-fluoro-3-methyl-phenyl)pyrazolo[4,3- 0.063b]pyridin-1-yl]ethanone; 711-Cyclopropyl-2-[6-(2-fluoro-3-methyl-phenyl)pyrazolo[4,3- 0.007b]pyridin-1-yl]ethanone; 721-Cyclopropyl-2-[6-(4-fluoro-2-methyl-phenyl)pyrazolo[4,3- 0.199b]pyridin-1-yl]ethanone; 73 1-Cyclopropyl-2-[6-[2-fluoro-3- 0.043(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1- yl]ethanone; 741-Cyclopropyl-2-[6-[4-fluoro-3- 0.036(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1- yl]ethanone; 752-[6-[4-Chloro-3-(trifluoromethyl)phenyl]pyrazolo[4,3- 0.076b]pyridin-1-yl]-1-cyclopropyl-ethanone; 761-Cyclopropyl-2-[6-[3-(difluoromethyl)-4-fluoro- 0.018phenyl]pyrazolo[4,3-b]pyridin-1-yl]ethanone; 771-Cyclopropyl-2-[6-[3-(difluoromethoxy)-4-fluoro- 0.014phenyl]pyrazolo[4,3-b]pyridin-1-yl]ethanone; 781-Cyclopropyl-2-[6-(4-fluoro-2,3-dimethyl- 0.085phenyl)pyrazolo[4,3-b]pyridin-1-yl]ethanone; 791-Cyclopropyl-2-[6-(2,3,4-trifluorophenyl)pyrazolo[4,3- 0.030b]pyridin-1-yl]ethanone; 80 (RS)-1-(Ethylsulfinylmethyl)-6-(3- 0.823fluorophenyl)pyrazolo[4,3-b]pyridine; 81(RS)-1-(Ethylsulfinylmethyl)-6-[3- 0.128(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridine; 82 (RS)6-(3,4-Difluorophenyl)-1- 0.893(ethylsulfinylmethyl)pyrazolo[4,3-b]pyridine; 83(RS)-6-(3-(Difluoromethyl)-4-fluorophenyl)-1- 0.034((ethylsulfinyl)methyl)-1H-pyrazolo[4,3-b]pyridine; 84(S*)-6-(3-(Difluoromethyl)-4-fluorophenyl)-1- 0.029((ethylsulfinyl)methyl)-1H-pyrazolo[4,3-b]pyridine; 85(R*)-6-(3-(Difluoromethyl)-4-fluorophenyl)-1- 0.066((ethylsulfinyl)methyl)-1H-pyrazolo[4,3-b]pyridine; 86(RS)-1-(Ethylsulfinylmethyl)-6-[2-fluoro-3- 0.080(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridine; 87(RS)-6-[4-Chloro-3-(difluoromethoxy)phenyl]-1- 0.109(ethylsulfinylmethyl)pyrazolo[4,3-b]pyridine; 88(RS)-1-(Ethylsulfinylmethyl)-6-(3,4,5- 0.736trifluorophenyl)pyrazolo[4,3-b]pyridine; 896-(4-Fluoro-3-methyl-phenyl)-1-(2- 0.754methoxyethyl)pyrazolo[4,3-b]pyridine; 90 (RS)-4-Methoxy-1-[6-[3- 1.420(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]butan- 2-ol; 91(RS)-1-[6-(3,4-Difluorophenyl)pyrazolo[4,3-b]pyridin-1- 0.526yl]butan-2-ol; 92 (RS)-1-[6-[3-(difluoromethoxy)-4-fluoro- 0.282phenyl]pyrazolo[4,3-b]pyridin-1-yl]butan-2-ol; 93 (RS)-1-[6-[4-Chloro-3-0.415 (difluoromethoxy)phenyl]pyrazolo[4,3-b]pyridin-1-yl]butan- 2-ol;94 (RS)-1-[6-(3,4-Difluorophenyl)-3-fluoro-pyrazolo[4,3- 0.965b]pyridin-1-yl]butan-2-ol; 95(RS)-1-[6-[3-(1,1-Difluoroethyl)phenyl]pyrazolo[4,3- 0.272b]pyridin-1-yl]butan-2-ol; 96(RS)-3-Methyl-1-(6-phenylpyrazolo[4,3-b]pyridin-1- 1.530 yl)butan-2-ol;97 (RS)-3-Methyl-1-[6-(3,4,5-trifluorophenyl)pyrazolo[4,3- 0.591b]pyridin-1-yl]butan-2-ol; 981-(2,2-Difluorobutyl)-6-[3-(difluoromethyl)-4-fluoro- 0.089phenyl]pyrazolo[4,3-b]pyridine; 991-(2,2-Difluorobutyl)-6-[3-(difluoromethoxy)-4-fluoro- 0.213phenyl]pyrazolo[4,3-b]pyridine; 100 (RS)-1-Cyclopropyl-2-[6-[3- 0.290(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]ethanol; 101(RS)-1-Cyclopropyl-2-[6-(4-fluoro-3-methyl- 0.167phenyl)pyrazolo[4,3-b]pyridin-1-yl]ethanol; 102(R)-1-Cyclopropyl-2-[6-(4-fluoro-3-methyl- 0.109phenyl)pyrazolo[4,3-b]pyridin-1-yl]ethanol; 103(S)-1-Cyclopropyl-2-[6-(4-fluoro-3-methyl- 0.272phenyl)pyrazolo[4,3-b]pyridin-1-yl]ethanol; 104(RS)-1-Cyclopropyl-2-(6-(3-(difluoromethyl)-4- 0.165fluorophenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl]ethan-1-ol; 105(E/Z)-N-Methoxy-3-methyl-1-[6-[3- 5.250(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]butan- 2-imine; 106(E/Z)-1-Cyclopropyl-2-[6-[3- 1.490(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1- yl]ethanone oxime; 107(E/Z)-1-Cyclopropyl-2-[6-[3-(difluoromethyl)-4-fluoro- 0.065phenyl]pyrazolo[4,3-b]pyridin-1-yl]ethanone oxime; 1081-(2-Cyclopropyl-2,2-difluoro-ethyl)-6[3-(difluoromethyl)- 0.0454-fluoro-phenyl]pyrazolo[4,3-b]pyridine; 1091-(2-Cyclopropyl-2,2-difluoro-ethyl)-6-[3- 0.069(difluoromethoxy)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridine; 1106-[3-(Difluoromethyl)-4-fluoro-phenyl]-1-[(3-methyloxetan- 2.0603-yl)methyl]pyrazolo[4,3-b]pyridine; 111(RS)-1-(Tetrahydrofuran-2-ylmethyl)-6-[3- 0.093(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridine; 112(RS)-6-[3-(Difluoromethoxy)-4-fluoro-phenyl]-1- 0.113(tetrahydrofuran-2-ylmethyl)pyrazolo[4,3-b]pyridine; 113(RS)-6-[3-(Difluoromethyl)-4-fluoro-phenyl]-1- 0.023(tetrahydrofuran-3-ylmethyl)pyrazolo[4,3-b]pyridine; 114(RS)-5-((6-(3-(Difluoromethoxy)-4-fluorophenyl)-1H- >2.99985pyrazolo[4,3-b]pyridin-1-yl)methyl)-1-methylpyrrolidin-2- one; 115(RS)-5-[[6-(Difluoromethyl)-4-fluoro- >2.99985phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-1-methyl- pyrrolidin-2-one;116 (RS)-3-[[6-[3-(Difluoromethyl)-4-fluoro- 0.303phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-1-methyl- pyrrolidin-2-one;117 (S)-3-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3- 1.210b]pyridin-1-yl]methyl]-1-methyl-pyrrolidin-2-one; 118(R)-3-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3- 0.125b]pyridin-1-yl]methyl]-1-methyl-pyrrolidin-2-one; 119(RS)-3-((6-(3-(Difluoromethoxy)-4-fluorophenyl)-1H- 0.352pyrazolo[4,3-b]pyridin-1-yl)methyl)-1-methylpyrrolidin-2- one; 120(RS)-4-[[6-[3-(Difluoromethyl)-4-fluoro- 0.089phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-1-methyl- pyrrolidin-2-one;121 (S)-4-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3- 0.685b]pyridin-1-yl]methyl]-1-methyl-pyrrolidin-2-one; 122(R)-4-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3- 0.120b]pyridin-1-yl]methyl]-1-methyl-pyrrolidin-2-one; 123(RS)-4-((6-(3-(difluoromethoxy)-4-fluorophenyl)-1H- 2.830pyrazolo[4,3-b]pyridin-1-yl)methyl)-3-methyloxazolidin-2- one; 124(RS)-4[[6-[3-(Difluoromethyl)-4-fluoro- 1.890phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-3-methyl- oxazolidin-2-one;125 (RS)-5-[[6-[3-(Difluoromethoxy)-4-fluoro- 0.498phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]oxazolidin-2- one; 126(RS)-5-[[6-[4-Chloro-3- 0.306(difluoromethoxy)phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]oxazolidin-2-one; 127(RS)-5-[[6-[3-(1,1-Difluoroethyl)-4-fluoro- 0.973phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]oxazolidin-2- one; 128(RS)-5-((6-(3-(Difluoromethoxy)-4-fluorophenyl)-1H- 0.165pyrazolo[4,3-b]pyridin-1-yl)methyl)-3-methyloxazolidin-2- one; 129(5R)-54[643-(Difluoromethyl)-4-fluoro- 0.030phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-3-methyl- oxazolidin-2-one;130 (5S)-5-[[6-[3-(Difluoromethyl)-4-fluoro- 0.478phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-3-methyl- oxazolidin-2-one;131 (RS)-54[6-[3-(Difluoromethyl)-4-fluoro- 0.193phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-3-ethyl- oxazolidin-2-one;132 (S)-5-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3- 1.430b]pyridin-1-yl]methyl]-3-ethyl-oxazolidin-2-one; 133(R)-5-[[643-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3- 0.204b]pyridin-1-yl]methyl]-3-ethyl-oxazolidin-2-one; 134(RS)-3-Cyclopropyl-5-[[6-[3-(difluoromethyl)-4-fluoro- 1.630phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]oxazolidin-2- one; 135(S)-3-Cyclopropyl-5-[[6-[3-(difluoromethyl)-4-fluoro- >2.99985phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]oxazolidin-2- one; 136(R)-3-Cyclopropyl-5-[[6-[3-(difluoromethyl)-4-fluoro- 0.997phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]oxazolidin-2- one; 1372-[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3- 0.036b]pyridin-1-yl]-1-(2-thienyl)ethanone; 1382-[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3- 0.100b]pyridin-1-yl]-1-(3-thienyl)ethanone; 1392-[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3- 0.118b]pyridin-1-yl]-1-(4-pyridyl)ethanone; 1402-(6-(3-(Difluoromethyl)-4-fluorophenyl)-1H-pyrazolo[4,3- 0.191b]pyridin-1-yl)-1-(3-fluoropyridin-2-yl)ethan-1-one; 1412-(6-(3-(Difluoromethyl)-4-fluorophenyl)-1H-pyrazolo[4,3- 0.409b]pyridin-1-yl)-1-(3,5-difluoropyridin-2-yl)ethan-1-one; and 1422-(6-(3-(Difluoromethyl)-4-fluorophenyl)-1H-pyrazolo[4,3- 0.074b]pyridin-1-yl)-1-(pyrazin-2-yl)ethan-1-one.

Protocol for Liver Microsomal Stability (Extraction Ratio)

Liver Microsomal Stability.

Microsomal stability studies (Chrovian et al, “1H-Pyrrolo[3,2-b]pyridineGluN2B-Selective Negative Allosteric Modulators”. ACS Med Chem Lett.2019 Jan. 10; 10(3):261-266) were conducted on a Biomek® FX RoboticLiquid Handling Workstation (Beckman Coulter, Brea, Calif.), whichconsists of a 96-channel pipette head, a 12-position workstation deck,and a plate incubator. Test compounds (1 μm) were spiked in a reactionmix consisting of 100 mM potassium phosphate buffer (pH 7.4), 3 mMMgCl₂, and 0.5 mg/mL liver microsomes from mouse, rat, and human (BDGentest). The reaction was brought to 37° C. and initiated by addingNADPH to a final concentration of 1 mM. After mixing on the plate deck,50 μL aliquots were excised from the reaction plate at 0, 5, 10, 20, 40,and 60 min and quenched with four volumes of acetonitrile spiked with500 μg/nL of the internal standard phenytoin. Quenched plates werecentrifuged at 5700 rpm for 10 min at 4° C., and supernatant was diluted1:3 in water before LC/MS/MS analysis. The compound half-lives werederived from plots of the ln of percent remaining compound over time todetermine the intrinsic clearance. The predicted hepatic clearance wasderived from the intrinsic clearance value using equations from thewell-stirred model (Current Drug Metabolism, 2008, 9, 940-951), where nocorrection was made plasma protein binding and the blood to plasmaconcentration ratio was assumed to be one. The extraction ratio (ER) wascalculated by dividing the predicted hepatic clearance by species bloodflow (Q), where Q is 90, 55, and 21.7 mL/min/kg for mouse, rat andhuman, respectively.

Results of the assay performed on the compounds of Examples are shown inTable 4.

Example # Extraction Ratio @ 1 μM 4 0.66 25 0.64 36 0.72 38 0.61 42 0.6361 0.43 78 0.52 85 0.46 86 0.50 131 0.58

Specific Embodiments

The present disclosure is exemplified by specific embodiments 1 to 27below.

-   1. A compound having the structure of Formula (I):

-   -   wherein    -   R¹ is H, halo, or CH₃;    -   Ar¹ is selected from the group consisting of:        -   (a) phenyl;        -   (b) phenyl substituted with one member selected from the            group consisting of: halo, C₁₋₆alkyl, C₁₋₆perhaloalkyl, and            OC₁₋₆perhaloalkyl;        -   (c) phenyl substituted with two or three members each            independently selected from the group consisting of: halo,            C₁₋₆alkyl, C₁₋₆perhaloalkyl, and OC₁₋₆perhaloalkyl; and        -   (d) thienyl substituted with one member selected from the            group consisting of: halo, and C₁₋₆alkyl;    -   R² is selected from the group consisting of:        -   (e)

wherein R^(a) is selected from the group consisting of: C₁₋₆alkyl;C₃₋₆cycloalkyl; thienyl; pyridyl; pyridyl substituted with one or two Fmembers; pyrazinyl;

-   -    wherein R is C₁₋₆alkyl;        -   (f) C₁₋₆alkyl substituted with one, two, or three members            each independently selected from the group consisting of:            OH, halo, OC₁₋₆alkyl, (═N—OH), (═N—OCH₃), and cyclopropyl;            and        -   (g) oxetanyl; oxetanyl substituted with C₁₋₆alkyl;            tetrahydrofuranyl; oxazolidinone; oxazolidinone substituted            with C₁₋₄alkyl, or cyclopropyl; and pyrrolidinone            substituted with C₁₋₄alkyl;        -   and pharmaceutically acceptable salts, solvates,            stereoisomers, isotopic variants, or N-oxides thereof.

-   2. The compound of embodiment 1, wherein R¹ is H.

-   3. The compound of embodiment 1, wherein R¹ is F.

-   4. The compound of embodiment 1, wherein R¹ is CH₃.

-   5. The compound of embodiment 1, wherein Ar¹ is phenyl.

-   6. The compound of embodiment 1, wherein Ar¹ is phenyl substituted    with one member selected from the group consisting of: F, CH₃, CF₂H,    CF₂CH₃, CF₃, and OCF₃.

-   7. The compound of embodiment 1, wherein Ar¹ is selected from the    group consisting of:

-   8. The compound of embodiment 1, wherein Ar¹ is phenyl substituted    with two members each independently selected from the group    consisting of: F, Cl, CH₃, CF₂H, CF₃, CF₂CH₃, and OCF₂H.-   9. The compound of embodiment 1, wherein Ar¹ is selected from the    group consisting of:

-   10. The compound of embodiment 1, wherein Ar¹ is phenyl substituted    with three members each independently selected from the group    consisting of: F and CH₃.-   11. The compound of embodiment 1, wherein Ar¹ is

-   12. The compound of embodiment 1, wherein Ar¹ is thienyl is    substituted with Cl or CH₃.-   13. The compound of embodiment 1, wherein Ar¹ is or.

-   14. The compound of embodiment 1, wherein R² is

-   15. The compound of embodiment 1, wherein R² is

-   16. The compound of embodiment 1, wherein R² is

-   17. The compound of embodiment 1, wherein R² is

-   18. The compound of embodiment 1, having the structure of Formula    (IA):

-   -   wherein    -   HAL is F or Cl;    -   R¹ is H, F, or CH₃;    -   R² is selected from the group consisting of:    -   (a) (S═O)CH₂CH₃; (SO₂)CH₂CH₃; or

wherein R^(a) is selected from the group consisting of: CH₃, CH₂CH₃,CH(CH₃)₂, cyclopropyl, cyclobutyl,

(b) CH₂OCH₃, CH(OH)(CH₂CH₃), CH(OH)CH(CH₃)₂, CF₂CH₂CH₃,CF₂(cyclopropyl), CH(OCH₃)(cyclopropyl), CH(OH)(cyclopropyl), or

and (c)

-   -   R^(c) is H, F or CH₃;    -   R^(d) is selected from the group consisting of: H, F, Cl, CH₃,        CF₂H, CF₂CH₃, CF₃, and OCF₂H; and    -   R^(e) is H or F; wherein when R^(e) is F, R^(c) is H;    -   and pharmaceutically acceptable salts, solvates, stereoisomers,        isotopic variants, or N-oxides thereof.

-   19. The compound of embodiment 18, where HAL is F; R is H; R^(c) is    H; and R^(e) is H.

-   20. The compound of embodiment 1, having the structure of Formula    (IB):

-   -   wherein    -   Ar¹ is selected from the group consisting of:        -   (a) phenyl, 3-methylphenyl, 2-fluorophenyl, 3-fluorophenyl,            3-(difluoromethyl)phenyl, 3-(1,1-difluoroethyl)phenyl,            3-(trifluoromethyl)phenyl, 3-(trifluoromethoxy)phenyl,            5-methyl-2-thienyl, or 5-chloro-2-thienyl; and        -   (b) 2-fluoro-3-methyl-phenyl, 2,3-difluorophenyl,            3,5-difluorophenyl, 3-chloro-2-fluoro-phenyl,            2-fluoro-3-(trifluoromethyl)phenyl,            4-chloro-3-(difluoromethoxy)phenyl, or            4-chloro-3-(trifluoromethyl)phenyl; and    -   R² is selected from the group consisting of: (S═O)CH₂CH₃,        (C═O)CH₂CH₃, (C═O)CH(CH₃)₂, and (C═O)cyclopropyl;    -   and pharmaceutically acceptable salts, solvates, stereoisomers,        isotopic variants, or N-oxides thereof.

-   21. A compound selected from the group consisting of:

-   1-[6-(3,5-Difluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]butan-2-one;

-   3-Methyl-1-[6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]butan-2-one;

-   (RS)-3-Methyl-1-[6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]butan-2-ol;

-   1-[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]butan-2-one;

-   (RS)-1-[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]butan-2-ol;

-   (E/Z)-3-Methyl-1-[6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]butan-2-one    oxime;

-   1-[6-(4-Fluoro-3-methyl-phenyl)pyrazolo[4,3-b]pyridin-1-yl]-3-methyl-butan-2-one;

-   (RS)-1-[6-(4-Fluoro-3-methyl-phenyl)pyrazolo[4,3-b]pyridin-1-yl]-3-methyl-butan-2-ol;

-   1-Cyclopropyl-2-[6-(3,4,5-trifluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]ethanone;

-   (RS)-1-Cyclopropyl-2-[6-(3,4,5-trifluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]ethanol;

-   (RS)-1-(2-Cyclopropyl-2-methoxy-ethyl)-6-(3,4,5-trifluorophenyl)pyrazolo[4,3-b]pyridine;

-   (RS)-6-[3-(Difluoromethoxy)-4-fluoro-phenyl]-1-(ethylsulfinylmethyl)pyrazolo[4,3-b]pyridine;

-   6-[3-(Difluoromethoxy)-4-fluoro-phenyl]-1-(ethylsulfonylmethyl)pyrazolo[4,3-b]pyridine;

-   2-[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1-(2-pyridyl)ethanone;

-   2-(6-(3-(Difluoromethyl)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)-1-(5-fluoropyridin-2-yl)ethan-1-one;

-   2-(6-(3-(Difluoromethyl)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)-1-(pyridin-3-yl)ethan-1-one;

-   (RS)-1-(Oxetan-2-ylmethyl)-6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridine;

-   (RS)-6-[3-(Difluoromethyl)-4-fluoro-phenyl]-1-(tetrahydrofuran-2-ylmethyl)pyrazolo[4,3-b]pyridine;

-   (RS)-4-[[6-[3-(Difluoromethoxy)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-1-methyl-pyrrolidin-2-one;

-   (RS)-5-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]oxazolidin-2-one;

-   (S)-5-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]oxazolidin-2-one;

-   (R)-5-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]oxazolidin-2-one;

-   1-[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]propan-2-one;

-   1-[6-(4-Fluoro-3-methyl-phenyl)pyrazolo[4,3-b]pyridin-1-yl]propan-2-one;

-   1-[6-[3-(Difluoromethoxy)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]propan-2-one;

-   1-[6-[4-Chloro-3-(difluoromethoxy)phenyl]pyrazolo[4,3-b]pyridin-1-yl]propan-2-one;

-   1-[6-(5-Chloro-2-thienyl)pyrazolo[4,3-b]pyridin-1-yl]butan-2-one;

-   1-[6-(4-Fluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]butan-2-one;

-   1-[6-(3-Fluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]butan-2-one;

-   1-[6-[3-(Difluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]butan-2-one;

-   1-[6-[3-(1,1-Difluoroethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]butan-2-one;

-   1-[6-(4-Fluoro-3-methyl-phenyl)pyrazolo[4,3-b]pyridin-1-yl]butan-2-one;

-   1-[6-(2,3-Difluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]butan-2-one;

-   1-[6-(3,4-Difluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]butan-2-one;

-   1-[6-(3,4-Difluorophenyl)-3-fluoro-pyrazolo[4,3-b]pyridin-1-yl]butan-2-one;

-   1-(6-(3-(Difluoromethyl)-4-fluorophenyl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-1-yl)butan-2-one;

-   1-[6-[3-(1,1-Difluoroethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]butan-2-one;

-   1-[6-[2-Fluoro-3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]butan-2-one;

-   1-[6-[4-Fluoro-3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]butan-2-one;

-   1-[6-[3-(Difluoromethoxy)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]butan-2-one;

-   1-[6-[4-Chloro-3-(difluoromethoxy)phenyl]pyrazolo[4,3-b]pyridin-1-yl]butan-2-one;

-   1-[6-(3,4,5-Trifluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]butan-2-one;

-   1-[6-(2,3,4-Trifluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]butan-2-one;

-   3-Methyl-1-(6-phenylpyrazolo[4,3-b]pyridin-1-yl)butan-2-one;

-   1-[6-(4-Fluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]-3-methyl-butan-2-one;

-   1-[6-(3-Fluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]-3-methyl-butan-2-one;

-   1-[6-[3-(Difluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]-3-methyl-butan-2-one;

-   1-[6-(2,3-Difluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]-3-methyl-butan-2-one;

-   1-[6-(3,4-Difluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]-3-methyl-butan-2-one;

-   1-[6-[2-Fluoro-3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]-3-methyl-butan-2-one;

-   1-[6-[4-Fluoro-3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]-3-methyl-butan-2-one;

-   1-[6-(4-Fluoro-2-methyl-phenyl)pyrazolo[4,3-b]pyridin-1-yl]-3-methyl-butan-2-one;

-   3-Methyl-1-[6-(3,4,5-trifluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]butan-2-one;

-   3-Methyl-1-[6-(2,3,4-trifluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]butan-2-one;

-   2-[6-(5-Chloro-2-thienyl)pyrazolo[4,3-b]pyridin-1-yl]-1-cyclopropyl-ethanone;

-   1-Cyclopropyl-2-[6-(5-methyl-2-thienyl)pyrazolo[4,3-b]pyridin-1-yl]ethanone;

-   1-Cyclopropyl-2-[6-(3-fluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]ethanone;

-   1-Cyclopropyl-2-[6-(2-fluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]ethanone;

-   1-Cyclopropyl-2-[6-(4-fluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]ethanone;

-   1-Cyclopropyl-2-[6-(m-tolyl)pyrazolo[4,3-b]pyridin-1-yl]ethanone;

-   1-Cyclopropyl-2-[6-[3-(difluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]ethanone;

-   1-Cyclopropyl-2-[6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]ethanone;

-   1-Cyclopropyl-2-[6-[3-(trifluoromethoxy)phenyl]pyrazolo[4,3-b]pyridin-1-yl]ethanone;

-   1-Cyclopropyl-2-[6-(2,3-difluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]ethanone;

-   1-Cyclopropyl-2-[6-(3,4-difluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]ethanone;

-   1-Cyclopropyl-2-[6-(3,5-difluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]ethanone;

-   2-[6-(3-Chloro-2-fluoro-phenyl)pyrazolo[4,3-b]pyridin-1-yl]-1-cyclopropyl-ethanone;

-   2-[6-(3-Chloro-4-fluoro-phenyl)pyrazolo[4,3-b]pyridin-1-yl]-1-cyclopropyl-ethanone;

-   1-Cyclopropyl-2-[6-(4-fluoro-3-methyl-phenyl)pyrazolo[4,3-b]pyridin-1-yl]ethanone;

-   1-Cyclobutyl-2-[6-(4-fluoro-3-methyl-phenyl)pyrazolo[4,3-b]pyridin-1-yl]ethanone;

-   1-Cyclopropyl-2-[6-(2-fluoro-3-methyl-phenyl)pyrazolo[4,3-b]pyridin-1-yl]ethanone;

-   1-Cyclopropyl-2-[6-(4-fluoro-2-methyl-phenyl)pyrazolo[4,3-b]pyridin-1-yl]ethanone;

-   1-Cyclopropyl-2-[6-[2-fluoro-3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]ethanone;

-   1-Cyclopropyl-2-[6-[4-fluoro-3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]ethanone;

-   2-[6-[4-Chloro-3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1-cyclopropyl-ethanone;

-   1-Cyclopropyl-2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]ethanone;

-   1-Cyclopropyl-2-[6-[3-(difluoromethoxy)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]ethanone;

-   1-Cyclopropyl-2-[6-(4-fluoro-2,3-dimethyl-phenyl)pyrazolo[4,3-b]pyridin-1-yl]ethanone;

-   1-Cyclopropyl-2-[6-(2,3,4-trifluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]ethanone;

-   (RS)-1-(Ethylsulfinylmethyl)-6-(3-fluorophenyl)pyrazolo[4,3-b]pyridine;

-   (RS)-1-(Ethylsulfinylmethyl)-6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridine;

-   (RS)    6-(3,4-Difluorophenyl)-1-(ethylsulfinylmethyl)pyrazolo[4,3-b]pyridine;

-   (RS)-6-(3-(Difluoromethyl)-4-fluorophenyl)-1-((ethylsulfinyl)methyl)-1H-pyrazolo[4,3-b]pyridine;

-   (S*)-6-(3-(Difluoromethyl)-4-fluorophenyl)-1-((ethylsulfinyl)methyl)-1H-pyrazolo[4,3-b]pyridine;

-   (R*)-6-(3-(Difluoromethyl)-4-fluorophenyl)-1-((ethylsulfinyl)methyl)-1H-pyrazolo[4,3-b]pyridine;

-   (RS)-1-(Ethylsulfinylmethyl)-6-[2-fluoro-3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridine;

-   (RS)-6-[4-Chloro-3-(difluoromethoxy)phenyl]-1-(ethylsulfinylmethyl)pyrazolo[4,3-b]pyridine;

-   (RS)-1-(Ethylsulfinylmethyl)-6-(3,4,5-trifluorophenyl)pyrazolo[4,3-b]pyridine;

-   6-(4-Fluoro-3-methyl-phenyl)-1-(2-methoxyethyl)pyrazolo[4,3-b]pyridine;

-   (RS)-4-Methoxy-1-[6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]butan-2-ol;

-   (RS)-1-[6-(3,4-Difluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]butan-2-ol;

-   (RS)-1-[6-[3-(Difluoromethoxy)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]butan-2-ol;

-   (RS)-1-[6-[4-Chloro-3-(difluoromethoxy)phenyl]pyrazolo[4,3-b]pyridin-1-yl]butan-2-ol;

-   (RS)-1-[6-(3,4-Difluorophenyl)-3-fluoro-pyrazolo[4,3-b]pyridin-1-yl]butan-2-ol;

-   (RS)-1-[6-[3-(1,1-Difluoroethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]butan-2-ol;

-   (RS)-3-Methyl-1-(6-phenylpyrazolo[4,3-b]pyridin-1-yl)butan-2-ol;

-   (RS)-3-Methyl-1-[6-(3,4,5-trifluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]butan-2-ol;

-   1-(2,2-Difluorobutyl)-6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridine;

-   1-(2,2-Difluorobutyl)-6-[3-(difluoromethoxy)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridine;

-   (RS)-1-Cyclopropyl-2-[6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]ethanol;

-   (RS)-1-Cyclopropyl-2-[6-(4-fluoro-3-methyl-phenyl)pyrazolo[4,3-b]pyridin-1-yl]ethanol;

-   (R)-1-Cyclopropyl-2-[6-(4-fluoro-3-methyl-phenyl)pyrazolo[4,3-b]pyridin-1-yl]ethanol;

-   (S)-1-Cyclopropyl-2-[6-(4-fluoro-3-methyl-phenyl)pyrazolo[4,3-b]pyridin-1-yl]ethanol;

-   (RS)-1-Cyclopropyl-2-(6-(3-(difluoromethyl)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)ethan-1-ol;

-   (E/Z)-N-Methoxy-3-methyl-1-[6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]butan-2-imine;

-   (E/Z)-1-Cyclopropyl-2-[6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]ethanone    oxime;

-   (E/Z)-1-Cyclopropyl-2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]ethanone    oxime;

-   1-(2-Cyclopropyl-2,2-difluoro-ethyl)-6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridine;

-   1-(2-Cyclopropyl-2,2-difluoro-ethyl)-6-[3-(difluoromethoxy)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridine;

-   6-[3-(Difluoromethyl)-4-fluoro-phenyl]-1-[(3-methyloxetan-3-yl)methyl]pyrazolo[4,3-b]pyridine;

-   (RS)-1-(Tetrahydrofuran-2-ylmethyl)-6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridine;

-   (RS)-6-[3-(Difluoromethoxy)-4-fluoro-phenyl]-1-(tetrahydrofuran-2-ylmethyl)pyrazolo[4,3-b]pyridine;

-   (RS)-6-[3-(Difluoromethyl)-4-fluoro-phenyl]-1-(tetrahydrofuran-3-ylmethyl)pyrazolo[4,3-b]pyridine;

-   (RS)-5-((6-(3-(Difluoromethoxy)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)methyl)-1-methylpyrrolidin-2-one;

-   (RS)-5-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-1-methyl-pyrrolidin-2-one;

-   (RS)-3-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-1-methyl-pyrrolidin-2-one;

-   (S)-3-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-1-methyl-pyrrolidin-2-one;

-   (R)-3-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-1-methyl-pyrrolidin-2-one;

-   (RS)-3-((6-(3-(Difluoromethoxy)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)methyl)-1-methylpyrrolidin-2-one;

-   (RS)-4-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-1-methyl-pyrrolidin-2-one;

-   (S)-4-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-1-methyl-pyrrolidin-2-one;

-   (R)-4-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-1-methyl-pyrrolidin-2-one;

-   (RS)-4-((6-(3-(difluoromethoxy)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)methyl)-3-methyloxazolidin-2-one;

-   (RS)-4-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-3-methyl-oxazolidin-2-one;

-   (RS)-5-[[6-[3-(Difluoromethoxy)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]oxazolidin-2-one;

-   (RS)-5-[[6-[4-Chloro-3-(difluoromethoxy)phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]oxazolidin-2-one;

-   (RS)-5-[[6-[3-(1,1-Difluoroethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]oxazolidin-2-one;

-   (RS)-5-((6-(3-(Difluoromethoxy)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)methyl)-3-methyloxazolidin-2-one;

-   (5R)-5-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-3-methyl-oxazolidin-2-one;

-   (5S)-5-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-3-methyl-oxazolidin-2-one;

-   (RS)-5-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-3-ethyl-oxazolidin-2-one;

-   (S)-5-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-3-ethyl-oxazolidin-2-one;

-   (R)-5-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-3-ethyl-oxazolidin-2-one;

-   (RS)-3-Cyclopropyl-5-[[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]oxazolidin-2-one;

-   (S)-3-Cyclopropyl-5-[[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]oxazolidin-2-one;

-   (R)-3-Cyclopropyl-5-[[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]oxazolidin-2-one;

-   2-[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1-(2-thienyl)ethanone;

-   2-[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1-(3-thienyl)ethanone;

-   2-[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1-(4-pyridyl)ethanone;

-   2-(6-(3-(Difluoromethyl)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)-1-(3-fluoropyridin-2-yl)ethan-1-one;

-   2-(6-(3-(Difluoromethyl)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)-1-(3,5-difluoropyridin-2-yl)ethan-1-one;

-   2-(6-(3-(Difluoromethyl)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)-1-(pyrazin-2-yl)ethan-1-one;    -   and pharmaceutically acceptable salts, solvates, stereoisomers,        isotopic variants, or N-oxides thereof.

-   22. A compound selected from the group consisting of:

-   1-[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]butan-2-one;

-   1-[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]propan-2-one;

-   1-[6-(3,4-Difluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]butan-2-one;

-   1-(6-(3-(Difluoromethyl)-4-fluorophenyl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-1-yl)butan-2-one;

-   1-[6-[3-(Difluoromethoxy)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]butan-2-one;

-   1-Cyclopropyl-2-[6-(4-fluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]ethanone;

-   1-Cyclopropyl-2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]ethanone;

-   (RS)-6-(3-(Difluoromethyl)-4-fluorophenyl)-1-((ethylsulfinyl)methyl)-1H-pyrazolo[4,3-b]pyridine;

-   (S*)-6-(3-(Difluoromethyl)-4-fluorophenyl)-1-((ethylsulfinyl)methyl)-1H-pyrazolo[4,3-b]pyridine;    and

-   (5R)-5-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-3-methyl-oxazolidin-2-one;    -   and pharmaceutically acceptable salts, solvates, stereoisomers,        isotopic variants, or N-oxides thereof.

-   23. A pharmaceutical composition comprising: (A) an effective amount    of at least one compound selected from compounds of Formula (I):

-   -   wherein    -   R¹ is H, halo, or CH₃;    -   Ar¹ is selected from the group consisting of:        -   (a) phenyl;        -   (b) phenyl substituted with one member selected from the            group consisting of: halo, C₁₋₆alkyl, C₁₋₆perhaloalkyl, and            OC₁₋₆perhaloalkyl;        -   (c) phenyl substituted with two or three members each            independently selected from the group consisting of: halo,            C₁₋₆alkyl, C₁₋₆perhaloalkyl, and OC₁₋₆perhaloalkyl; and        -   (d) thienyl substituted with one member selected from the            group consisting of: halo, and C₁₋₆alkyl;    -   R² is selected from the group consisting of:        -   (e)

wherein R is selected from the group consisting of: C₁₋₆alkyl;C₃₋₆cycloalkyl; thienyl; pyridyl; pyridyl substituted with one or two Fmembers; pyrazinyl;

-   -    wherein R^(b) is C₁₋₆alkyl;        -   (f) C₁₋₆alkyl substituted with one, two, or three members            each independently selected from the group consisting of:            OH, halo, OC₁₋₆alkyl, (═N—OH), (═N—OCH₃), and cyclopropyl;            and        -   (g) oxetanyl; oxetanyl substituted with C₁₋₆alkyl;            tetrahydrofuranyl; oxazolidinone; oxazolidinone substituted            with C₁₋₄alkyl, or cyclopropyl; and pyrrolidinone            substituted with C₁₋₄alkyl;        -   and pharmaceutically acceptable salts, stereoisomers,            isotopic variants, N-oxides, or solvates of compounds of            Formula (I);        -   (B) at least one pharmaceutically acceptable excipient.

-   24. A pharmaceutical composition comprising an effective amount of    at least one compound of embodiment 21 and at least one    pharmaceutically acceptable excipient.

-   25. A method of treating a subject suffering from or diagnosed with    a disease, disorder, or medical condition mediated by GluN2B    receptor activity, comprising administering to a subject in need of    such treatment an effective amount of at least one compound selected    from compounds of Formula (I):

-   -   wherein    -   R¹ is H, halo, or CH₃;    -   Ar¹ is selected from the group consisting of:        -   (a) phenyl;        -   (b) phenyl substituted with one member selected from the            group consisting of: halo, C₁₋₆alkyl, C₁₋₆perhaloalkyl, and            OC₁₋₆perhaloalkyl;        -   (c) phenyl substituted with two or three members each            independently selected from the group consisting of: halo,            C₁₋₆alkyl, C₁₋₆perhaloalkyl, and OC₁₋₆perhaloalkyl; and        -   (d) thienyl substituted with one member selected from the            group consisting of: halo, and C₁₋₆alkyl;    -   R² is selected from the group consisting of:        -   (e)

-   -   -    wherein R^(a) is selected from the group consisting of:            C₁₋₆alkyl; C₃₋₆cycloalkyl; thienyl; pyridyl; pyridyl            substituted with one or two F members; pyrazinyl;

-   -   -    wherein R^(b) is C₁₋₆alkyl;        -   (f) C₁₋₆alkyl substituted with one, two, or three members            each independently selected from the group consisting of:            OH, halo, OC₁₋₆alkyl, (═N—OH), (═N—OCH₃), and cyclopropyl;            and        -   (g) oxetanyl; oxetanyl substituted with C₁₋₆alkyl;            tetrahydrofuranyl; oxazolidinone; oxazolidinone substituted            with C₁₋₄alkyl, or cyclopropyl; and pyrrolidinone            substituted with C₁₋₄alkyl;        -   and pharmaceutically acceptable salts, stereoisomers,            isotopic variants, N-oxides, or solvates of compounds of            Formula (I).

-   26. The method of embodiment 25, wherein the disorder, disease or    condition mediated by the GluN2B receptor is selected from the group    consisting of: bipolar disorder, major depressive disorder,    treatment-resistant depression, post-partum depression, seasonal    affective disorder, Alzheimer's disease, Parkinson's disease,    Huntington's chorea, multiple sclerosis, cognitive impairment, head    injury, spinal cord injury, stroke, epilepsy, dyskinesias,    amyotrophic lateral sclerosis, neurodegeneration associated with    bacterial or chronic infections, pain, diabetic neuropathy,    migraine, cerebral ischemia, schizophrenia, encephalitis, autism and    autism spectrum disorders, memory and learning disorders, obsessive    compulsive disorder, attention deficit hyperactivity disorder (ADHD)    and addictive illnesses.

-   27. The method of embodiment 25 wherein the disorder, disease or    condition is selected from the group consisting of    treatment-resistant depression, major depressive disorder and    bipolar disorder.

The present disclosure is further exemplified by specific embodiments 1to 45 below.

-   1. A compound having the structure of Formula (I):

or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopicvariant, or N-oxide thereof,whereinR¹ is H, halo, or CH₃;Ar¹ is selected from the group consisting of:

-   -   (a) phenyl;    -   (b) phenyl substituted with one member selected from the group        consisting of: halo, C₁₋₆alkyl, C₁₋₆perhaloalkyl, and        OC₁₋₆perhaloalkyl;    -   (c) phenyl substituted with two or three members each        independently selected from the group consisting of: halo,        C₁₋₆alkyl, C₁₋₆perhaloalkyl, and OC₁₋₆perhaloalkyl; and    -   (d) thienyl substituted with one member selected from the group        consisting of: halo, and C₁₋₆alkyl;        R² is selected from the group consisting of:    -   (e)

wherein R^(a) is selected from the group consisting of: C₁₋₆alkyl;C₃₋₆cycloalkyl; thienyl; pyridyl; pyridyl substituted with one or two Fmembers; pyrazinyl;

wherein R^(b) is C₁₋₆alkyl;

-   -   (f) C₁₋₆alkyl substituted with one, two, or three members each        independently selected from the group consisting of: OH, halo,        OC₁₋₆alkyl, (═N—OH), (═N—OCH₃), and cyclopropyl; and    -   (g) oxetanyl; oxetanyl substituted with C₁₋₆alkyl;        tetrahydrofuranyl; oxazolidinone; oxazolidinone substituted with        C₁₋₄alkyl, or cyclopropyl; and pyrrolidinone substituted with        C₁₋₄alkyl.

-   2. The compound of embodiment 1 or a pharmaceutically acceptable    salt, solvate, stereoisomer, isotopic variant, or N-oxide thereof,    wherein R¹ is H.

-   3. The compound of embodiment 1 or a pharmaceutically acceptable    salt, solvate, stereoisomer, isotopic variant, or N-oxide thereof,    wherein R¹ is F.

-   4. The compound of embodiment 1 or a pharmaceutically acceptable    salt, solvate, stereoisomer, isotopic variant, or N-oxide thereof,    wherein R¹ is CH₃.

-   5. The compound of any one of embodiments 1 to 4, or a    pharmaceutically acceptable salt, solvate, stereoisomer, isotopic    variant, or N-oxide thereof, wherein Ar^(l) is phenyl.

-   6. The compound of any one of embodiments 1 to 4, or a    pharmaceutically acceptable salt, solvate, stereoisomer, isotopic    variant, or N-oxide thereof, wherein Ar^(l) is phenyl substituted    with one member selected from the group consisting of: F, CH₃, CF₂H,    CF₂CH₃, CF₃, and OCF₃.

-   7. The compound of any one of embodiments 1 to 4, or a    pharmaceutically acceptable salt, solvate, stereoisomer, isotopic    variant, or N-oxide thereof, wherein Ar^(l) is selected from the    group consisting of:

-   8. The compound of any one of embodiments 1 to 4, or a    pharmaceutically acceptable salt, solvate, stereoisomer, isotopic    variant, or N-oxide thereof, wherein Ar¹ is phenyl substituted with    two members each independently selected from the group consisting    of: F, Cl, CH₃, CF₂H, CF₃, CF₂CH₃, and OCF₂H.-   9. The compound of any one of embodiments 1 to 4, or a    pharmaceutically acceptable salt, solvate, stereoisomer, isotopic    variant, or N-oxide thereof, wherein Ar¹ is selected from the group    consisting of:

-   10. The compound of any one of embodiments 1 to 4, or a    pharmaceutically acceptable salt, solvate, stereoisomer, isotopic    variant, or N-oxide thereof, wherein Ar¹ is phenyl substituted with    three members each independently selected from the group consisting    of: F and CH₃.-   11. The compound of any one of embodiments 1 to 4, or a    pharmaceutically acceptable salt, solvate, stereoisomer, isotopic    variant, or N-oxide thereof, wherein Ar¹ is

-   12. The compound of any one of embodiments 1 to 4, or a    pharmaceutically acceptable salt, solvate, stereoisomer, isotopic    variant, or N-oxide thereof, wherein Ar¹ is thienyl is substituted    with Cl or CH₃.-   13. The compound of any one of embodiments 1 to 4, or a    pharmaceutically acceptable salt, solvate, stereoisomer, isotopic    variant, or N-oxide thereof, wherein Ar¹ is

-   14. The compound of any one of embodiments 1 to 13, or a    pharmaceutically acceptable salt, solvate, stereoisomer, isotopic    variant, or N-oxide thereof, wherein R² is

-   15. The compound of any one of embodiments 1 to 13, or a    pharmaceutically acceptable salt, solvate, stereoisomer, isotopic    variant, or N-oxide thereof, wherein R² is

-   16. The compound of any one of embodiments 1 to 13, or a    pharmaceutically acceptable salt, solvate, stereoisomer, isotopic    variant, or N-oxide thereof, wherein R² is

-   17. The compound of any one of embodiments 1 to 13, or a    pharmaceutically acceptable salt, solvate, stereoisomer, isotopic    variant, or N-oxide thereof, wherein R² is

-   18. The compound of embodiment or a pharmaceutically acceptable    salt, solvate, stereoisomer, isotopic variant, or N-oxide thereof,    having the structure of Formula (IA):

-   -   wherein    -   HAL is F or Cl;    -   R¹ is H, F, or CH₃;    -   R² is selected from the group consisting of:    -   (a) (S═O)CH₂CH₃; (SO₂)CH₂CH₃; or

wherein R^(a) is selected from the group consisting of: CH₃, CH₂CH₃,CH(CH₃)₂, cyclopropyl, cyclobutyl,

-   -   (b) CH₂OCH₃, CH(OH)(CH₂CH₃), CH(OH)CH(CH₃)₂, CF₂CH₂CH₃,        CF₂(cyclopropyl), or

and (c)

-   -   R^(c) is H, F or CH₃;

R^(d) is selected from the group consisting of: H, F, Cl, CH₃, CF₂H,CF₂CH₃, CF₃, and OCF₂H; and

-   -   R^(e) is H or F; wherein when R^(e) is F, R^(c) is H.

-   19. The compound of embodiment 18 or a pharmaceutically acceptable    salt, solvate, stereoisomer, isotopic variant, or N-oxide thereof,    where HAL is F; R¹ is H; R^(c) is H; and R^(e) is H.

-   20. The compound of embodiment 1 or a pharmaceutically acceptable    salt, solvate, stereoisomer, isotopic variant, or N-oxide thereof,    having the structure of Formula (IB):

-   -   wherein    -   Ar^(l) is selected from the group consisting of:        -   (a) phenyl, 3-methylphenyl, 2-fluorophenyl, 3-fluorophenyl,            3-(difluoromethyl)phenyl, 3-(1,1-difluoroethyl)phenyl,            3-(trifluoromethyl)phenyl, 3-(trifluoromethoxy)phenyl,            5-methyl-2-thienyl, or 5-chloro-2-thienyl; and        -   (b) 2-fluoro-3-methyl-phenyl, 2,3-difluorophenyl,            3,5-difluorophenyl, 3-chloro-2-fluoro-phenyl,            2-fluoro-3-(trifluoromethyl)phenyl,            4-chloro-3-(difluoromethoxy)phenyl, or            4-chloro-3-(trifluoromethyl)phenyl; and    -   R² is selected from the group consisting of: (S═O)CH₂CH₃,        (C═O)CH₂CH₃, (C═O)CH(CH₃)₂, and (C═O)cyclopropyl.

-   21. A compound selected from the compounds in Table 1 and    pharmaceutically acceptable salts, solvates, stereoisomers, isotopic    variants, and N-oxides thereof.

-   22. The compound of any one of embodiments 1 to 21, or a    pharmaceutically acceptable salt or solvate thereof.

-   23. The compound of any one of embodiments 1 to 21, or a    pharmaceutically acceptable salt or N-oxide thereof.

-   24. The compound of any one of embodiments 1 to 21, or a    pharmaceutically acceptable salt thereof.

-   25. The compound of any one of embodiments 1 to 21.

-   26. A pharmaceutically acceptable salt of the compound of any one of    embodiments 1 to 21.

-   27. A pharmaceutical composition comprising the compound of any one    of embodiments 1 to 21, or a pharmaceutically acceptable salt,    solvate, isotopic variant, or N-oxide thereof, and a    pharmaceutically acceptable excipient.

-   28. A pharmaceutical composition comprising the compound of any one    of embodiments 1 to 21, or a pharmaceutically acceptable salt or    solvate thereof, and a pharmaceutically acceptable excipient.

-   29. A pharmaceutical composition comprising the compound of any one    of embodiments 1 to 21, or a pharmaceutically acceptable salt or    N-oxide thereof, and a pharmaceutically acceptable excipient.

-   30. A pharmaceutical composition comprising the compound of any one    of embodiments 1 to 21, or a pharmaceutically acceptable salt    thereof, and a pharmaceutically acceptable excipient.

-   31. A pharmaceutical composition comprising the compound of any one    of embodiments 1 to 21 and a pharmaceutically acceptable excipient.

-   32. A pharmaceutical composition comprising a pharmaceutically    acceptable salt of the compound of any one of embodiments 1 to 21,    and a pharmaceutically acceptable excipient.

-   33. A unit dosage form comprising a therapeutically effective amount    of the pharmaceutical composition of any one of embodiments 27 to    32.

-   34. A method of treating a subject suffering from or diagnosed with    a disease, disorder, or medical condition mediated by GluN2B    receptor activity, comprising administering to the subject a    therapeutically effective amount of the compound of any one of    embodiments 1 to 21, or a pharmaceutically acceptable salt, solvate,    isotopic variant, or N-oxide thereof.

-   35. A method of treating a subject suffering from or diagnosed with    a disease, disorder, or medical condition mediated by GluN2B    receptor activity, comprising administering to the subject a    therapeutically effective amount of the compound of any one of    embodiments 1 to 21, or a pharmaceutically acceptable salt, or    solvate thereof.

-   36. A method of treating a subject suffering from or diagnosed with    a disease, disorder, or medical condition mediated by GluN2B    receptor activity, comprising administering to the subject a    therapeutically effective amount of the compound of any one of    embodiments 1 to 21, or a pharmaceutically acceptable salt or    N-oxide thereof.

-   37. A method of treating a subject suffering from or diagnosed with    a disease, disorder, or medical condition mediated by GluN2B    receptor activity, comprising administering to the subject a    therapeutically effective amount of the compound of any one of    embodiments 1 to 21, or a pharmaceutically acceptable salt thereof.

-   38. A method of treating a subject suffering from or diagnosed with    a disease, disorder, or medical condition mediated by GluN2B    receptor activity, comprising administering to the subject a    therapeutically effective amount of the pharmaceutical composition    of any one of embodiments 27 to 32 or the unit dosage form of    embodiment 33.

-   39. The method of any one of embodiments 34 to 38, wherein the    disease, disorder or medical condition mediated by GluN2B receptor    activity comprises bipolar disorder, major depressive disorder,    treatment-resistant depression, a mood disorder, post-partum    depression, seasonal affective disorder, Alzheimer's disease,    Parkinson's disease, Huntington's chorea, multiple sclerosis,    cognitive impairment, head injury, spinal cord injury, stroke,    epilepsy, dyskinesias, amyotrophic lateral sclerosis,    neurodegeneration associated with a bacterial or chronic infection,    pain, diabetic neuropathy, migraine, cerebral ischemia,    schizophrenia, encephalitis, autism or an autism spectrum disorder,    a memory disorder, a learning disorder, obsessive compulsive    disorder, attention deficit hyperactivity disorder (ADHD) or an    addictive illness.

-   40. The method of embodiment 39, wherein the disease, disorder or    medical condition mediated by GluN2B receptor activity comprises    bipolar disorder, a mood disorder, treatment resistant depression,    major depressive disorder, or epilepsy.

-   41. The method of embodiment 39, wherein the disease, disorder or    medical condition mediated by GluN2B receptor activity comprises    bipolar disorder.

-   42. The method of embodiment 39, wherein the disease, disorder or    medical condition mediated by GluN2B receptor activity comprises a    mood disorder.

-   43. The method of embodiment 39, wherein the disease, disorder or    medical condition mediated by GluN2B receptor activity comprises    treatment resistant depression.

-   44. The method of embodiment 39, wherein the disease, disorder or    medical condition mediated by GluN2B receptor activity comprises    major depressive disorder.

-   45. The method of embodiment 39, wherein the disease, disorder or    medical condition mediated by GluN2B receptor activity comprises    epilepsy.

What is claimed is:
 1. A compound having the structure of Formula (I):

or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:R¹ is H, halo, or CH₃; Ar¹ is selected from the group consisting of: (a)phenyl; (b) phenyl substituted with one member selected from the groupconsisting of: halo, C₁₋₆alkyl, C₁₋₆perhaloalkyl, and OC₁₋₆perhaloalkyl;(c) phenyl substituted with two or three members each independentlyselected from the group consisting of: halo, C₁₋₆alkyl,C₁₋₆perhaloalkyl, and OC₁₋₆perhaloalkyl; and (d) thienyl substitutedwith one member selected from the group consisting of: halo andC₁₋₆alkyl; R² is selected from the group consisting of: (a)

 wherein R^(a) is selected from the group consisting of: C₁₋₆alkyl;C₃₋₆cycloalkyl; thienyl; pyridyl; pyridyl substituted with one or two Fmembers; pyrazinyl;

 wherein R^(b) is C₁₋₆alkyl; (b) C₁₋₆alkyl substituted with one, two, orthree members each independently selected from the group consisting of:OH, halo, OC₁₋₆alkyl, (═N—OH), (═N—OCH₃), and cyclopropyl; and (c)oxetanyl; oxetanyl substituted with C₁₋₆alkyl; tetrahydrofuranyl;oxazolidinone; oxazolidinone substituted with C₁₋₄alkyl or cyclopropyl;and pyrrolidinone substituted with C₁₋₄alkyl.
 2. The compound of claim 1or a pharmaceutically acceptable salt, solvate, stereoisomer thereof,wherein R¹ is H.
 3. The compound of claim 1 or a pharmaceuticallyacceptable salt or stereoisomer thereof, wherein R¹ is F.
 4. Thecompound of claim 1 or a pharmaceutically acceptable salt orstereoisomer thereof, wherein R¹ is CH₃.
 5. The compound of claim 1 or apharmaceutically acceptable salt or stereoisomer thereof, wherein Ar¹ isphenyl.
 6. The compound of claim 1 or a pharmaceutically acceptable saltor stereoisomer thereof, wherein Ar¹ is phenyl substituted with onemember selected from the group consisting of: F, CH₃, CF₂H, CF₂CH₃, CF₃,and OCF₃.
 7. The compound of claim 1 or a pharmaceutically acceptablesalt or stereoisomer thereof, wherein Ar¹ is:


8. The compound of claim 1 or a pharmaceutically acceptable salt orstereoisomer thereof, wherein Ar¹ is phenyl substituted with two memberseach independently selected from the group consisting of: F, Cl, CH₃,CF₂H, CF₃, CF₂CH₃, and OCF₂H.
 9. The compound of claim 1 or apharmaceutically acceptable salt or stereoisomer thereof, wherein Ar¹is:


10. The compound of claim 1 or a pharmaceutically acceptable salt orstereoisomer thereof, wherein Ar¹ is phenyl substituted with threemembers each independently selected from the group consisting of: F andCH₃.
 11. The compound of claim 1 or a pharmaceutically acceptable saltor stereoisomer thereof, wherein Ar¹ is


12. The compound of claim 1 or a pharmaceutically acceptable salt orstereoisomer thereof, wherein Ar¹ is thienyl substituted with Cl or CH₃.13. The compound of claim 1 or a pharmaceutically acceptable salt orstereoisomer thereof, wherein Ar¹ is


14. The compound of claim 1 or a pharmaceutically acceptable salt orstereoisomer thereof, wherein R² is


15. The compound of claim 1 or a pharmaceutically acceptable salt orstereoisomer thereof, wherein R² is


16. The compound of claim 1 or a pharmaceutically acceptable salt orstereoisomer thereof, wherein R² is


17. The compound of claim 1 or a pharmaceutically acceptable salt orstereoisomer thereof, wherein R² is


18. The compound of claim 1 having the structure of Formula (IA):

or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:HAL is F or Cl; R¹ is H, F, or CH₃; R² is selected from the groupconsisting of: (a) (S═O)CH₂CH₃; (SO₂)CH₂CH₃; and

wherein R^(a) is selected from the group consisting of: CH₃, CH₂CH₃,CH(CH₃)₂, cyclopropyl, cyclobutyl,

(b) CH₂OCH₃; CH(OH)(CH₂CH₃); CH(OH)CH(CH₃)₂; CF₂CH₂CH₃;CF₂(cyclopropyl); CH(OCH₃)(cyclopropyl); CH(OH)(cyclopropyl); and

and (c)

R^(c) is H, F or CH₃; R^(d) is selected from the group consisting of: H,F, Cl, CH₃, CF₂H, CF₂CH₃, CF₃, and OCF₂H; and R^(e) is H or F; whereinwhen R^(c) is F, R^(c) is H.
 19. The compound of claim 18 or apharmaceutically acceptable salt or stereoisomer thereof, where HAL isF; R¹ is H; R^(c) is H; and R^(e) is H.
 20. The compound of claim 1having the structure of Formula (IB):

or a Pharmaceutically acceptable salt or stereoisomer thereof, wherein:Ar¹ is selected from the group consisting of: (a) phenyl,3-methylphenyl, 2-fluorophenyl, 3-fluorophenyl,3-(difluoromethyl)phenyl, 3-(1,1-difluoroethyl)phenyl,3-(trifluoromethyl)phenyl, 3-(trifluoromethoxy)phenyl,5-methyl-2-thienyl, and; 5-chloro-2-thienyl; and (b)2-fluoro-3-methyl-phenyl, 2,3-difluorophenyl, 3,5-difluorophenyl,3-chloro-2-fluoro-phenyl, 2-fluoro-3-(trifluoromethyl)phenyl,4-chloro-3-(difluoromethoxy)phenyl, and;4-chloro-3-(trifluoromethyl)phenyl; and R² is selected from the groupconsisting of: (S═O)CH₂CH₃, (C═O)CH₂CH₃, (C═O)CH(CH₃)₂, and(C═O)cyclopropyl.
 21. A compound selected from the group consisting of:1-[6-(3,5-Difluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]butan-2-one;3-Methyl-1-[6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]butan-2-one;(RS)-3-Methyl-1-[6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]butan-2-ol;1-[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]butan-2-one;(RS)-1-[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]butan-2-ol;(E/Z)-3-Methyl-1-[6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]butan-2-oneoxime;1-[6-(4-Fluoro-3-methyl-phenyl)pyrazolo[4,3-b]pyridin-1-yl]-3-methyl-butan-2-one;(RS)-1-[6-(4-Fluoro-3-methyl-phenyl)pyrazolo[4,3-b]pyridin-1-yl]-3-methyl-butan-2-ol;1-Cyclopropyl-2-[6-(3,4,5-trifluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]ethanone;(RS)-1-Cyclopropyl-2-[6-(3,4,5-trifluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]ethanol;(RS)-1-(2-Cyclopropyl-2-methoxy-ethyl)-6-(3,4,5-trifluorophenyl)pyrazolo[4,3-b]pyridine;(RS)-6-[3-(Difluoromethoxy)-4-fluoro-phenyl]-1-(ethylsulfinylmethyl)pyrazolo[4,3-b]pyridine;6-[3-(Difluoromethoxy)-4-fluoro-phenyl]-1-(ethylsulfonylmethyl)pyrazolo[4,3-b]pyridine;2-[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1-(2-pyridyl)ethanone;2-(6-(3-(Difluoromethyl)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)-1-(5-fluoropyridin-2-yl)ethan-1-one;2-(6-(3-(Difluoromethyl)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)-1-(pyridin-3-yl)ethan-1-one;(RS)-1-(Oxetan-2-ylmethyl)-6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridine;(RS)-6-[3-(Difluoromethyl)-4-fluoro-phenyl]-1-(tetrahydrofuran-2-ylmethyl)pyrazolo[4,3-b]pyridine;(RS)-4-[[6-[3-(Difluoromethoxy)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-1-methyl-pyrrolidin-2-one;(RS)-5-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]oxazolidin-2-one;(S)-5-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]oxazolidin-2-one;(R)-5-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]oxazolidin-2-one;1-[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]propan-2-one;1-[6-(4-Fluoro-3-methyl-phenyl)pyrazolo[4,3-b]pyridin-1-yl]propan-2-one;1-[6-[3-(Difluoromethoxy)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]propan-2-one;1-[6-[4-Chloro-3-(difluoromethoxy)phenyl]pyrazolo[4,3-b]pyridin-1-yl]propan-2-one;1-[6-(5-Chloro-2-thienyl)pyrazolo[4,3-b]pyridin-1-yl]butan-2-one;1-[6-(4-Fluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]butan-2-one;1-[6-(3-Fluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]butan-2-one;1-[6-[3-(Difluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]butan-2-one;1-[6-[3-(1,1-Difluoroethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]butan-2-one;1-[6-(4-Fluoro-3-methyl-phenyl)pyrazolo[4,3-b]pyridin-1-yl]butan-2-one;1-[6-(2,3-Difluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]butan-2-one;1-[6-(3,4-Difluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]butan-2-one;1-[6-(3,4-Difluorophenyl)-3-fluoro-pyrazolo[4,3-b]pyridin-1-yl]butan-2-one;1-(6-(3-(Difluoromethyl)-4-fluorophenyl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-1-yl)butan-2-one;1-[6-[3-(1,1-Difluoroethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]butan-2-one;1-[6-[2-Fluoro-3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]butan-2-one;1-[6-[4-Fluoro-3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]butan-2-one;1-[6-[3-(Difluoromethoxy)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]butan-2-one;1-[6-[4-Chloro-3-(difluoromethoxy)phenyl]pyrazolo[4,3-b]pyridin-1-yl]butan-2-one;1-[6-(3,4,5-Trifluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]butan-2-one;1-[6-(2,3,4-Trifluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]butan-2-one;3-Methyl-1-(6-phenylpyrazolo[4,3-b]pyridin-1-yl)butan-2-one;1-[6-(4-Fluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]-3-methyl-butan-2-one;1-[6-(3-Fluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]-3-methyl-butan-2-one;1-[6-[3-(Difluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]-3-methyl-butan-2-one;1-[6-(2,3-Difluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]-3-methyl-butan-2-one;1-[6-(3,4-Difluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]-3-methyl-butan-2-one;1-[6-[2-Fluoro-3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]-3-methyl-butan-2-one;1-[6-[4-Fluoro-3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]-3-methyl-butan-2-one;1-[6-(4-Fluoro-2-methyl-phenyl)pyrazolo[4,3-b]pyridin-1-yl]-3-methyl-butan-2-one;3-Methyl-1-[6-(3,4,5-trifluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]butan-2-one;3-Methyl-1-[6-(2,3,4-trifluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]butan-2-one;2-[6-(5-Chloro-2-thienyl)pyrazolo[4,3-b]pyridin-1-yl]-1-cyclopropyl-ethanone;1-Cyclopropyl-2-[6-(5-methyl-2-thienyl)pyrazolo[4,3-b]pyridin-1-yl]ethanone;1-Cyclopropyl-2-[6-(3-fluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]ethanone;1-Cyclopropyl-2-[6-(2-fluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]ethanone;1-Cyclopropyl-2-[6-(4-fluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]ethanone;1-Cyclopropyl-2-[6-(m-tolyl)pyrazolo[4,3-b]pyridin-1-yl]ethanone;1-Cyclopropyl-2-[6-[3-(difluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]ethanone;1-Cyclopropyl-2-[6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]ethanone;1-Cyclopropyl-2-[6-[3-(trifluoromethoxy)phenyl]pyrazolo[4,3-b]pyridin-1-yl]ethanone;1-Cyclopropyl-2-[6-(2,3-difluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]ethanone;1-Cyclopropyl-2-[6-(3,4-difluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]ethanone;1-Cyclopropyl-2-[6-(3,5-difluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]ethanone;2-[6-(3-Chloro-2-fluoro-phenyl)pyrazolo[4,3-b]pyridin-1-yl]-1-cyclopropyl-ethanone;2-[6-(3-Chloro-4-fluoro-phenyl)pyrazolo[4,3-b]pyridin-1-yl]-1-cyclopropyl-ethanone;1-Cyclopropyl-2-[6-(4-fluoro-3-methyl-phenyl)pyrazolo[4,3-b]pyridin-1-yl]ethanone;1-Cyclobutyl-2-[6-(4-fluoro-3-methyl-phenyl)pyrazolo[4,3-b]pyridin-1-yl]ethanone;1-Cyclopropyl-2-[6-(2-fluoro-3-methyl-phenyl)pyrazolo[4,3-b]pyridin-1-yl]ethanone;1-Cyclopropyl-2-[6-(4-fluoro-2-methyl-phenyl)pyrazolo[4,3-b]pyridin-1-yl]ethanone;1-Cyclopropyl-2-[6-[2-fluoro-3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]ethanone;1-Cyclopropyl-2-[6-[4-fluoro-3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]ethanone;2-[6-[4-Chloro-3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1-cyclopropyl-ethanone;1-Cyclopropyl-2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]ethanone;1-Cyclopropyl-2-[6-[3-(difluoromethoxy)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]ethanone;1-Cyclopropyl-2-[6-(4-fluoro-2,3-dimethyl-phenyl)pyrazolo[4,3-b]pyridin-1-yl]ethanone;1-Cyclopropyl-2-[6-(2,3,4-trifluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]ethanone;(RS)-1-(Ethylsulfinylmethyl)-6-(3-fluorophenyl)pyrazolo[4,3-b]pyridine;(RS)-1-(Ethylsulfinylmethyl)-6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridine;(RS)6-(3,4-Difluorophenyl)-1-(ethylsulfinylmethyl)pyrazolo[4,3-b]pyridine;(RS)-6-(3-(Difluoromethyl)-4-fluorophenyl)-1-((ethylsulfinyl)methyl)-1H-pyrazolo[4,3-b]pyridine;(S*)-6-(3-(Difluoromethyl)-4-fluorophenyl)-1-((ethylsulfinyl)methyl)-1H-pyrazolo[4,3-b]pyridine;(R*)-6-(3-(Difluoromethyl)-4-fluorophenyl)-1-((ethylsulfinyl)methyl)-1H-pyrazolo[4,3-b]pyridine;(RS)-1-(Ethylsulfinylmethyl)-6-[2-fluoro-3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridine;(RS)-6-[4-Chloro-3-(difluoromethoxy)phenyl]-1-(ethylsulfinylmethyl)pyrazolo[4,3-b]pyridine;(RS)-1-(Ethylsulfinylmethyl)-6-(3,4,5-trifluorophenyl)pyrazolo[4,3-b]pyridine;6-(4-Fluoro-3-methyl-phenyl)-1-(2-methoxyethyl)pyrazolo[4,3-b]pyridine;(RS)-4-Methoxy-1-[6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]butan-2-ol;(RS)-1-[6-(3,4-Difluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]butan-2-ol;(RS)-1-[6-[3-(Difluoromethoxy)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]butan-2-ol;(RS)-1-[6-[4-Chloro-3-(difluoromethoxy)phenyl]pyrazolo[4,3-b]pyridin-1-yl]butan-2-ol;(RS)-1-[6-(3,4-Difluorophenyl)-3-fluoro-pyrazolo[4,3-b]pyridin-1-yl]butan-2-ol;(RS)-1-[6-[3-(1,1-Difluoroethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]butan-2-ol;(RS)-3-Methyl-1-(6-phenylpyrazolo[4,3-b]pyridin-1-yl)butan-2-ol;(RS)-3-Methyl-1-[6-(3,4,5-trifluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]butan-2-ol;1-(2,2-Difluorobutyl)-6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridine;1-(2,2-Difluorobutyl)-6-[3-(difluoromethoxy)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridine;(RS)-1-Cyclopropyl-2-[6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]ethanol;(RS)-1-Cyclopropyl-2-[6-(4-fluoro-3-methyl-phenyl)pyrazolo[4,3-b]pyridin-1-yl]ethanol;(R)-1-Cyclopropyl-2-[6-(4-fluoro-3-methyl-phenyl)pyrazolo[4,3-b]pyridin-1-yl]ethanol;(S)-1-Cyclopropyl-2-[6-(4-fluoro-3-methyl-phenyl)pyrazolo[4,3-b]pyridin-1-yl]ethanol;(RS)-1-Cyclopropyl-2-(6-(3-(difluoromethyl)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)ethan-1-ol;(E/Z)-N-Methoxy-3-methyl-1-[6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]butan-2-imine;(E/Z)-1-Cyclopropyl-2-[6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]ethanoneoxime;(E/Z)-1-Cyclopropyl-2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]ethanoneoxime;1-(2-Cyclopropyl-2,2-difluoro-ethyl)-6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridine;1-(2-Cyclopropyl-2,2-difluoro-ethyl)-6-[3-(difluoromethoxy)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridine;6-[3-(Difluoromethyl)-4-fluoro-phenyl]-1-[(3-methyloxetan-3-yl)methyl]pyrazolo[4,3-b]pyridine;(RS)-1-(Tetrahydrofuran-2-ylmethyl)-6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridine;(RS)-6-[3-(Difluoromethoxy)-4-fluoro-phenyl]-1-(tetrahydrofuran-2-ylmethyl)pyrazolo[4,3-b]pyridine;(RS)-6-[3-(Difluoromethyl)-4-fluoro-phenyl]-1-(tetrahydrofuran-3-ylmethyl)pyrazolo[4,3-b]pyridine;(RS)-5-((6-(3-(Difluoromethoxy)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)methyl)-1-methylpyrrolidin-2-one;(RS)-5-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-1-methyl-pyrrolidin-2-one;(RS)-3-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-1-methyl-pyrrolidin-2-one;(S)-3-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-1-methyl-pyrrolidin-2-one;(R)-3-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-1-methyl-pyrrolidin-2-one;(RS)-3-((6-(3-(Difluoromethoxy)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)methyl)-1-methylpyrrolidin-2-one;(RS)-4-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-1-methyl-pyrrolidin-2-one;(S)-4-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-1-methyl-pyrrolidin-2-one;(R)-4-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-1-methyl-pyrrolidin-2-one;(RS)-4-((6-(3-(difluoromethoxy)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)methyl)-3-methyloxazolidin-2-one;(RS)-4-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-3-methyl-oxazolidin-2-one;(RS)-5-[[6-[3-(Difluoromethoxy)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]oxazolidin-2-one;(RS)-5-[[6-[4-Chloro-3-(difluoromethoxy)phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]oxazolidin-2-one;(RS)-5-[[6-[3-(1,1-Difluoroethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]oxazolidin-2-one;(RS)-5-((6-(3-(Difluoromethoxy)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)methyl)-3-methyloxazolidin-2-one;(5R)-5-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-3-methyl-oxazolidin-2-one;(5S)-5-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-3-methyl-oxazolidin-2-one;(RS)-5-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-3-ethyl-oxazolidin-2-one;(S)-5-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-3-ethyl-oxazolidin-2-one;(R)-5-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-3-ethyl-oxazolidin-2-one;(RS)-3-Cyclopropyl-5-[[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]oxazolidin-2-one;(S)-3-Cyclopropyl-5-[[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]oxazolidin-2-one;(R)-3-Cyclopropyl-5-[[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]oxazolidin-2-one;2-[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1-(2-thienyl)ethanone;2-[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1-(3-thienyl)ethanone;2-[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]-1-(4-pyridyl)ethanone;2-(6-(3-(Difluoromethyl)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)-1-(3-fluoropyridin-2-yl)ethan-1-one;2-(6-(3-(Difluoromethyl)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)-1-(3,5-difluoropyridin-2-yl)ethan-1-one;2-(6-(3-(Difluoromethyl)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)-1-(pyrazin-2-yl)ethan-1-one;and pharmaceutically acceptable salts and stereoisomers thereof.
 22. Acompound selected from the group consisting of:1-[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]butan-2-one;1-[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]propan-2-one;1-[6-(3,4-Difluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]butan-2-one;1-(6-(3-(Difluoromethyl)-4-fluorophenyl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-1-yl)butan-2-one;1-[6-[3-(Difluoromethoxy)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]butan-2-one;1-Cyclopropyl-2-[6-(4-fluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]ethanone;1-Cyclopropyl-2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]ethanone;(RS)-6-(3-(Difluoromethyl)-4-fluorophenyl)-1-((ethylsulfinyl)methyl)-1H-pyrazolo[4,3-b]pyridine;(S*)-6-(3-(Difluoromethyl)-4-fluorophenyl)-1-((ethylsulfinyl)methyl)-1H-pyrazolo[4,3-b]pyridine;(5R)-5-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-3-methyl-oxazolidin-2-one;and pharmaceutically acceptable salts and stereoisomers thereof.
 23. Apharmaceutical composition comprising: (A) at least one compoundselected from compounds of Formula (I):

and pharmaceutically acceptable salts and stereoisomers of compounds ofFormula (I), wherein: R¹ is H, halo, or CH₃; Ar¹ is selected from thegroup consisting of: (a) phenyl; (b) phenyl substituted with one memberselected from the group consisting of: halo, C₁₋₆alkyl,C₁₋₆perhaloalkyl, and OC₁₋₆perhaloalkyl; (c) phenyl substituted with twoor three members each independently selected from the group consistingof: halo, C₁₋₆alkyl, C₁₋₆perhaloalkyl, and OC₁₋₆perhaloalkyl; and (d)thienyl substituted with one member selected from the group consistingof: halo and C₁₋₆alkyl; R² is selected from the group consisting of: (a)

 wherein R^(a) is selected from the group consisting of: C₁₋₆alkyl;C₃₋₆cycloalkyl; thienyl; pyridyl; pyridyl substituted with one or two Fmembers; pyrazinyl;

 wherein R^(b) is C₁₋₆alkyl; (b) C₁₋₆alkyl substituted with one, two, orthree members each independently selected from the group consisting of:OH, halo, OC₁₋₆alkyl, (═N—OH), (═N—OCH₃), and cyclopropyl; and (c)oxetanyl; oxetanyl substituted with C₁₋₆alkyl; tetrahydrofuranyl;oxazolidinone; oxazolidinone substituted with C₁₋₄alkyl or cyclopropyl;and pyrrolidinone substituted with C₁₋₄alkyl; and (B) at least onepharmaceutically acceptable excipient.
 24. A pharmaceutical compositioncomprising at least one compound of claim 21 or a pharmaceuticallyacceptable salt or stereoisomer thereof, and at least onepharmaceutically acceptable excipient.
 25. A method of treating asubject suffering from or diagnosed with treatment-resistant depression,comprising administering to the subject an effective amount of acompound of claim 1 or a pharmaceutically acceptable salt orstereoisomer thereof.
 26. A method of treating a subject suffering fromor diagnosed with major depressive disorder, comprising administering tothe subject an effective amount of a compound of claim 1 or apharmaceutically acceptable salt or stereoisomer thereof.